Biomedicines doi: 10.3390/biomedicines12030680
Authors: Randolph Stone Emily C. Saathoff David A. Larson John T. Wall Nathan A. Wienandt Skuli Magnusson Hilmar Kjartansson Robert J. Christy Shanmugasundaram Natesan
The extent and depth of burn injury may mandate temporary use of cadaver skin (allograft) to protect the wound and allow the formation of granulation tissue while split-thickness skin grafts (STSGs) are serially harvested from the same donor areas. However, allografts are not always available and have a high cost, hence the interest in identifying more economical, readily available products that serve the same function. This study evaluated intact fish skin graft (IFSG) as a temporary cover to prepare the wound bed for STSG application. Thirty-six full-thickness (FT) 5 × 5 cm burn wounds were created on the dorsum of six anesthetized Yorkshire pigs on day −1. To mimic the two-stage clinical situation, on day 0, wounds were excised down to a bleeding wound bed and a temporary cover (either IFSG or cadaver porcine skin) was applied; then, on day 7, wounds were debrided to a viable wound bed prior to the application of autologous 1.5:1 meshed STSG (mSTSG). Rechecks were performed on days 14, 21, 28, 45, and 60 with digital images, non-invasive measurements, and punch biopsies. The IFSG created a granulated wound bed receptive to the application of an mSTSG. FT burn wounds treated with an IFSG had similar outcome measures, including contraction rates, trans-epidermal water loss (TEWL) measurements, hydration, and blood perfusion levels, compared to cadaver skin-treated burn wounds. Pathology scoring indicated significant differences between the allograft- and IFSG-treated wounds on day 7, with the IFSG having increased angiogenesis, granulation tissue formation, and immune cells. Pathology scoring indicated no significant differences once mSTSGs were applied to wounds. The IFSG performed as well as cadaver skin as a temporary cover and was not inferior to the standard of care, suggesting the potential to transition IFSGs into clinical use for burns.
]]>Biomedicines doi: 10.3390/biomedicines12030679
Authors: Sheng-Te Wang Ying-Ying Wang Jia-Rong Huang Yu-Bin Shu Ke He Zhi Shi
Colorectal cancer is a global malignancy with a high incidence and mortality rate. THZ2, a small inhibitor targeted CDK7, could inhibit multiple human tumor growths including small cell lung cancer, triple-negative breast cancer, ovarian cancer. However, the effect of THZ2 on inflammation, especially on colitis-associated colorectal cancer, is still unknown. In this study, we assessed the anti-inflammatory and anti-tumor effect of THZ2 in the mouse models of dextran sulfate sodium (DSS)-induced acute colitis and azoxymethane (AOM)/DSS-induced colitis-associated colorectal cancer. We found that THZ2 ameliorated inflammatory symptoms, including bleeding and diarrhea, in mouse models of DSS-induced acute colitis and AOM/DSS-induced colorectal cancer. The results of Western blot and immunohistochemistry showed that THZ2 rescued the up-regulated expression of COX2, IL-6, β-catenin, and snail in the mouse models. Moreover, THZ2 inhibits the development of colorectal cancer in the mouse model of AOM/DSS-induced colitis-associated colorectal cancer. Generally, THZ2 not only can inhibit DSS-induced colitis, but also can hinder AOM/DSS-induced colorectal cancer.
]]>Biomedicines doi: 10.3390/biomedicines12030678
Authors: Xi Chen Ying Song Guanghui Chen Baoliang Zhang Yang Bai Chuiguo Sun Dongwei Fan Zhongqiang Chen
Oxeiptosis is a reactive oxygen species (ROS)-induced pathway of cell death. The involvement of circular RNAs (circRNAs) has been confirmed in the incidence and progression of intervertebral disc degeneration (IVDD). However, whether oxeiptosis occurs in IVDD and how circRNAs regulate oxeiptosis is still unclear. In this study, we discovered that oxeiptosis could be induced in nucleus pulposus cells (NPCs), and circFOXO3 was significantly upregulated after oxeiptosis induction. Transfection using circFOXO3 small interfering RNA (siRNA) significantly inhibited oxeiptosis in NPCs. Mechanistically, circFOXO3 upregulated acid-sensing ion channel subunit 1 (ASIC1) expression by functioning as a molecular sponge for miR-185-3p and miR-939-5p. Subsequent rescue experiments validated that circFOXO3 could regulate oxeiptosis in NPCs via the miR-185-3p/miR-939-5p-ASIC1 axis. Further research on ASIC1 functions indicated that this regulation was achieved by affecting the Calcium ion (Ca2+) influx mediated by ASIC1. A mouse IVDD model was established, and silencing circFOXO3 in vivo was found to inhibit IVDD development and the activation of the oxeiptosis-related pathway. Overall, circFOXO3 is one of the factors contributing to the progression of IVDD by mediating oxeiptosis.
]]>Biomedicines doi: 10.3390/biomedicines12030677
Authors: Alessandra Della Vecchia Ciro De Luca Lucrezia Becattini Letizia Curto Elena Ferrari Gabriele Siciliano Sara Gori Filippo Baldacci
The study aimed to evaluate the effects of monoclonal antibodies (mAbs) acting on the calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRP/R mAbs) on migraine comorbidities of depression, anxiety, and fatigue in patients resistant to traditional therapies. The issue addressed in this study is pivotal to unveiling the role of this neurotransmitter beyond pain processing. We conducted an open-label prospective study assessing comorbidities in patients with high frequency (HFEM) and chronic migraine (CM), medication overuse headache (MOH), and resistance to traditional prophylaxis. All patients were treated with anti-CGRP/R mAbs for 3 months. Seventy-seven patients were enrolled with either HFEM (21%) or CM (79%) with or without MOH (56% and 44%, respectively). We identified 21 non-responders (27%) and 56 responders (73%), defined on the reduction ≥50% of headache frequency. The two groups were highly homogeneous for the investigated comorbidities. Disease severity in terms of headache frequency, migraine-related disability, and affective comorbid symptoms was reduced in both groups with different thresholds; allodynia and fatigue were ameliorated only in responders. We found that anti-CGRP/R antibodies improved pain together with affection, fatigue, and sensory sensitization in a cohort of migraine patients resistant to traditional prophylaxis. Our results offer novel perspectives on the early efficacy of anti-CGRP/R mAbs in difficult-to-treat patients focusing on clinical features other than pain relief.
]]>Biomedicines doi: 10.3390/biomedicines12030676
Authors: Mihai Popescu Angelica Bratu Mihaela Agapie Tudor Borjog Mugurel Jafal Romina-Marina Sima Carmen Orban
Acute liver failure represents a life-threatening organ dysfunction with high mortality rates and an urgent need for liver transplantation. The etiology of the disease varies widely depending on various socio-economic factors and is represented mainly by paracetamol overdose and other drug-induced forms of liver dysfunction in the developed world and by viral hepatitis and mushroom poisoning in less developed countries. Current medical care constitutes either specific antidotes or supportive measures to ensure spontaneous recovery. Although it has been proven to have beneficial effects in paracetamol-induced liver failure, N-acetylcysteine is widely used for all forms of acute liver failure. Despite this, few well-designed studies have been conducted on the assessment of the potential benefits, dose regimens, or route of administration of N-acetylcysteine in non-acetaminophen liver failure. This review aims to summarize the current evidence behind the use of this drug in different forms of liver failure.
]]>Biomedicines doi: 10.3390/biomedicines12030675
Authors: Beata Wojtczak Karolina Sutkowska-Stępień Mateusz Głód Krzysztof Kaliszewski Krzysztof Sutkowski Marcin Barczyński
Thyroid surgery rates have tripled over the past three decades, making it one of the most frequently performed procedures within general surgery. Thyroid surgery is associated with the possibility of serious postoperative complications which have a significant impact on the patient’s quality of life. Recurrent laryngeal nerve (RLN) palsy and external branch of the superior laryngeal nerve (EBSLN) palsy are, next to hypoparathyroidism and postoperative bleeding, some of the most common complications. The introduction of neuromonitoring into thyroid surgery, which enabled both the confirmation of anatomical integrity and the assessment of laryngeal nerve function, was a milestone that began a new era in thyroid surgery. The International Neural Monitoring Study Group has produced a standardization of the technique of RLN and EBSLN monitoring during thyroid and parathyroid surgery, which in turn increased the prevalence of neural monitoring during thyroidectomy. The current status of IONM and the benefits of its use have been presented in this publication.
]]>Biomedicines doi: 10.3390/biomedicines12030674
Authors: Masroor Badshah Jibriil Ibrahim Nguok Su Penny Whiley Ralf Middendorff Michael Whittaker Betty Exintaris
Overactive bladder (OAB) is an age-related disorder characterised by unstable bladder contractions resulting in disruptive lower urinary tract symptoms (LUTS), thus creating a profound impact on an individual’s quality of life. The development of LUTS may be linked to the overexpression of oxytocin receptors (OXTRs) within the bladder detrusor muscle, resulting in increased baseline myogenic tone. Thus, it is hypothesised that targeting OXTRs within the bladder using oxytocin antagonists may attenuate myogenic tone within the bladder, thereby providing a new therapeutic avenue for treating OAB. Organ bath contractility and immunohistochemistry techniques were conducted on bladder tissue sourced from young rats (7–8 weeks and 10–12 weeks) and older rats (4–5 months and 7–9 months). Organ bath studies revealed that oxytocin (OT) significantly increased bladder contractions, which were significantly attenuated by [β-Mercapto-β,β-cyclopentamethylenepropionyl1, O-Me-Tyr2, Orn8]-Oxytocin) (1 µM) (**** p < 0.0001) and atosiban (10 µM) in both young and older rats (** p < 0.01); in contrast, cligosiban (1 µM and 10 µM) did not inhibit OT-induced contractions in both young and older rats (p ≥ 0.05). Interestingly, cligosiban (1 µM and 10 µM) significantly reduced the frequency of spontaneous contractions within the bladder of both young (*** p < 0.001) and older rats (**** p < 0.0001), while atosiban (10 µM) only demonstrated this effect in older rats (** p < 0.01). Furthermore, immunohistochemistry (IHC) analysis revealed significant colocalization of nuclear-specific oxytocin receptors (OXTRs) in the contractile (smooth muscle) cells within young (** p < 0.01) and older rats (* p < 0.05), indicating OT may be a key modulator of bladder contractility.
]]>Biomedicines doi: 10.3390/biomedicines12030673
Authors: Madline P. Gund Jusef Naim Antje Lehmann Matthias Hannig Markus Lange Axel Schindler Stefan Rupf
Several studies have shown that cold atmospheric plasma (CAP) treatment can favourably modify titanium surfaces to promote osteoblast colonization. The aim of this study was to investigate the initial attachment of primary human osteoblasts to plasma-treated titanium. Micro-structured titanium discs were treated with cold atmospheric plasma followed by the application of primary human osteoblasts. The microwave plasma source used in this study uses helium as a carrier gas and was developed at the Leibniz Institute for Surface Modification in Leipzig, Germany. Primary human osteoblasts were analyzed by fluorescence and cell biological tests (alkaline phosphatase activity and cell proliferation using WST-1 assay). The tests were performed after 4, 12, and 24 h and showed statistically significant increased levels of cell activity after plasma treatment. The results of this study indicate that plasma treatment improves the initial attachment of primary human osteoblasts to titanium. For the first time, the positive effect of cold atmospheric plasma treatment of micro-structured titanium on the initial colonization with primary human osteoblasts has been demonstrated. Overall, this study demonstrates the excellent biocompatibility of micro-structured titanium. The results of this study support efforts to use cold atmospheric plasmas in implantology, both for preimplantation conditioning and for regeneration of lost attachment due to peri-implantitis.
]]>Biomedicines doi: 10.3390/biomedicines12030671
Authors: Víctor Riquelme-Aguado Alazne Zabarte-del Campo Guillermo Baviano-Klett Josué Fernández-Carnero Antonio Gil-Crujera Francisco Gómez-Esquer
Fibromyalgia (FM) is a chronic pain syndrome hypothesized to arise from a state of neurogenic inflammation. Mechanisms responsible for pain, as well as psychological variables, are typically altered in this condition. The main objective of this research was to explore somatosensory and psychological alterations in women with FM. The secondary objective was to carry out a secondary analysis to correlate the different variables studied and delve into the influences between them. The relationship between different psychological variables in fibromyalgia is not clear in the previous scientific literature. Forty-four individuals participated, of which twenty-two were controls and twenty-two were women with fibromyalgia. The main outcome measures were the Numeric Pain Rating Scale, Fibromyalgia Impact Questionnaire, pressure pain threshold, conditioned pain modulation, anxiety and depression symptoms, catastrophizing and kinesiophobia cognitions. The main analysis showed that there is a moderate correlation between the psychological variables of depression and fear of movement and the ability to modulate pain. There is also a moderately inverse correlation between pain catastrophizing cognitions and pain intensity/disability. Multiple moderate and strong correlations were found among the various psychological variables studied. FM patients exhibit somatosensory alterations alongside negative psychological symptoms that influence the experience of pain, and they may perpetuate the state of neurogenic inflammation.
]]>Biomedicines doi: 10.3390/biomedicines12030672
Authors: Marius Militaru Daniel Florin Lighezan Cristina Tudoran Anda Gabriela Militaru
(1) Background: Cognitive decline (CD), considered a precursory state of dementia, is frequently encountered in patients with diabetes mellitus type 2 (DM-2) and might even have a higher prevalence in those with associated atrial fibrillation (AF). In this study, we aimed to research if the association of DM-2 and AF favors a precocious onset of CD. (2) Methods: This study was conducted on 160 patients, featuring 50 with DM-2, 54 with DM-2 and AF, and 56 subjects without DM-2 and AF, all evaluated clinically and with five neuropsychiatric scales. (3) Results: The Mini-Mental-State-Examination (MMSE), Montreal Cognitive Assessment (MoCA), Activities of Daily Living Score (ADL), Instrumental Activities of Daily Living Score (IADL), and Geriatric Depression Scale (GDS-15) were significantly altered in patients with DM-2 and AF in comparison to patients without these diseases. The logistic regression model indicated that, in patients with DM-2 and AF, an increase of one year in age is associated with a 7.3% augmentation of the risk of a precocious onset of CD (MMSE < 27). (4) Conclusions: CD is more frequent in patients with DM-2, especially when associated with AF, versus those without DM-2 and AF. Our findings suggest that an older age and associated dyslipidemia represent risk factors for CD in patients with DM-2.
]]>Biomedicines doi: 10.3390/biomedicines12030670
Authors: Manuela De Michele Paola Piscopo Matteo Costanzo Svetlana Lorenzano Alessio Crestini Roberto Rivabene Valeria Manzini Luca Petraglia Marta Iacobucci Irene Berto Oscar Gaetano Schiavo Antonella Conte Daniele Belvisi Alfredo Berardelli Danilo Toni
Background: Ischemic stroke may trigger neuroplastic changes via proliferation, migration towards the lesion, and differentiation of neuroprogenitor cells into mature neurons. Repetitive Transcranial Magnetic Stimulation (rTMS) may promote brain plasticity. This study aimed to assess rTMS’s effect on post-stroke endogenous neuroplasticity by dosing plasma miRs 17~92, Netrin-1, Sema3A, and BDNF. Methods: In this case-controlled study, we randomized 19 ischemic stroke patients within five days from symptoms onset (T0) to neuronavigated-rTMS or sham stimulation. Stimulation was applied on the stroke hemisphere daily between the 7th and 14th day from stroke onset. Blood samples were collected at T0, before the first rTMS section (T7), and at the end of the last rTMS session (T14). Five healthy controls were also enrolled in this study. Results: Of 19 patients, 10 received rTMS and 9 sham stimulation. Compared with the sham group, in the rTMS group, plasma levels of miRs17~92 and Ntn-1 significantly increased whereas Sema3A levels tended to decrease. In multivariate linear regression analyses, rTMS was independently related to Ntn-1 and miR-25 levels at T14. Conclusions: We found an association between rTMS and neurogenesis/axonogenesis biomarker enhancement. Our preliminary data suggest that rTMS may positively interfere with natural endogenous plasticity phenomena of the post-ischemic human brain.
]]>Biomedicines doi: 10.3390/biomedicines12030669
Authors: Piotr J. Błoński Anna M. Czarnecka Krzysztof Ostaszewski Anna Szumera-Ciećkiewicz Piotr Rutkowski
Neoadjuvant systemic therapy is emerging as the best medical practice in patients with resectable stage III melanoma. As different regimens are expected to become available in this approach, the improved optimization of treatment strategies is required. Personalization of care in each individual patient—by precisely determining the disease-related risk and the most efficient therapeutic approach—is expected to minimize disease recurrence, but also the incidence of treatment-related adverse events and the extent of surgical intervention. This can be achieved through validation and clinical application of predictive and prognostic biomarkers. For immune checkpoint inhibitors, there are no validated predictive biomarkers until now. Promising predictive molecular biomarkers for neoadjuvant immunotherapy are tumor mutational burden and the interferon-gamma pathway expression signature. Pathological response to neoadjuvant treatment is a biomarker of a favorable prognosis and surrogate endpoint for recurrence-free survival in clinical trials. Despite the reliability of these biomarkers, risk stratification and response prediction in the neoadjuvant setting are still unsatisfactory and represent a critical knowledge gap, limiting the development of optimized personalized strategies in everyday practice.
]]>Biomedicines doi: 10.3390/biomedicines12030668
Authors: Hammed Ayansola Edith J. Mayorga Younggeon Jin
Intestinal epithelial cell activities during homeostasis and regeneration are well described, but their potential interactions with stromal cells remain unresolved. Exploring the functions of these heterogeneous intestinal mesenchymal stromal cells (iMSCs) remains challenging. This difficulty is due to the lack of specific markers for most functionally homogenous subpopulations. In recent years, however, novel clustering techniques such as single-cell RNA sequencing (scRNA-seq), fluorescence-activated cell sorting (FACS), confocal microscope, and computational remodeling of intestinal anatomy have helped identify and characterize some specific iMSC subsets. These methods help researchers learn more about the localization and functions of iMSC populations during intestinal morphogenic and homeostatic conditions. Consequently, it is imperative to understand the cellular pathways that regulate their activation and how they interact with surrounding cellular components, particularly during intestinal epithelial regeneration after mucosal injury. This review provides insights into the spatial distribution and functions of identified iMSC subtypes. It focuses on their involvement in intestinal morphogenesis, homeostasis, and regeneration. We reviewed related signaling mechanisms implicated during epithelial and subepithelial stromal cell crosstalk. Future research should focus on elucidating the molecular intermediates of these regulatory pathways to open a new frontier for potential therapeutic targets that can alleviate intestinal mucosa-related injuries.
]]>Biomedicines doi: 10.3390/biomedicines12030667
Authors: Petr Kelbich Eliska Vanaskova Karel Hrach Jan Krejsek Frantisek Smisko Pavla Hruskova Eva Hanuljakova Tomas Novotny
Neutrophils are frequently found in the cytological picture of synovial fluid in several joint pathologies, and a higher proportion of them can even wrongly indicate these cases as purulent inflammation. For reliable differentiation between purulent and non-purulent cases, we use the cytological energy analysis of the synovial fluid. Using this method, we examined 350 knee joint synovial fluid samples. Overall, we found that the percentage of neutrophils ranged between 20.0% and 50.0% in 44 (12.6%) cases and was above 50.0% in 231 (66.0%) cases. In the same group, only 85 (24.3%) highly anaerobic synovial fluid samples were evaluated as purulent inflammation, and another 17 (4.9%) cases were evaluated as very likely purulent inflammation. Further, we quantified the immediate risk of purulent inflammation using the “purulent score” (PS). Of the total of 350 samples, 103 (29.4%) cases were classified as having a very high risk of purulent inflammation (PS = 4), 53 (15.1%) cases were classified as having a significant risk of purulent inflammation (PS = 3), 17 (4.9%) cases were classified as having a moderate risk of purulent inflammation (PS = 2), and 75 (21.4%) cases were classified as having no immediate risk of purulent inflammation (PS = 1). Based on our results and analyses, the cytological energy analysis of synovial fluid is an effective method that can be used to detect and specify joint inflammation and the risk of septic arthritis development.
]]>Biomedicines doi: 10.3390/biomedicines12030666
Authors: Ahmad Almhdie-Imjabbar Hechmi Toumi Eric Lespessailles
Imaging biomarkers permit improved approaches to identify the most at-risk patients encountering knee osteoarthritis (KOA) progression. This study aimed to investigate the utility of trabecular bone texture (TBT) extracted from plain radiographs, associated with a set of clinical, biochemical, and radiographic data, as a predictor of long-term radiographic KOA progression. We used data from the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium dataset. The reference model made use of baseline TBT parameters adjusted for clinical covariates and radiological scores. Several models based on a combination of baseline and 24-month TBT variations (TBT∆TBT) were developed using logistic regression and compared to those based on baseline-only TBT parameters. All models were adjusted for baseline clinical covariates, radiological scores, and biochemical descriptors. The best overall performances for the prediction of radio-symptomatic, radiographic, and symptomatic progression were achieved using TBT∆TBT parameters solely, with area under the ROC curve values of 0.658 (95% CI: 0.612–0.705), 0.752 (95% CI: 0.700–0.804), and 0.698 (95% CI: 0.641–0.756), respectively. Adding biochemical markers did not significantly improve the performance of the TBT∆TBT-based model. Additionally, when TBT values were taken from the entire subchondral bone rather than just the medial, lateral, or central compartments, better results were obtained.
]]>Biomedicines doi: 10.3390/biomedicines12030665
Authors: Yordan Sbirkov Murad Redzheb Nico Forraz Colin McGuckin Victoria Sarafian
Technologies and biomaterials for 3D bioprinting have been developing extremely quickly in the past decade as they hold great potential in tissue engineering. This, together with the possibility to differentiate stem cells of different origin into any cell type, raises the hopes in regenerative medicine once again after the initial breakthrough with stem cells in the 1980s. Nevertheless, three decades of 3D bioprinting experiments have shown that the production of functional tissues would take a longer time than anticipated. Cartilage, one of the simplest tissues in the body, consists of only one cell type. It is not vascularised and innervated and does not have lymphatic vessels either, which makes it a perfect target tissue for successful implantation. The tremendous amount of work since the beginning of this century, combining the efforts of bioengineers, material scientists, biologists, and physicians, has culminated in multiple proof-of-concept constructs that have been implanted in animals. However, there is no single reproducible, standardised, widely accessible and accepted strategy that can be readily applied in the clinic. In this review, we focus on the current progress in the field of the 3D biofabrication of articular cartilage and critically assess failures and future challenges.
]]>Biomedicines doi: 10.3390/biomedicines12030664
Authors: Wenkai Shao Ping Wang Xiao Lv Bo Wang Song Gong Yong Feng
Osteonecrosis of the femoral head (ONFH) is a disabling disease characterized by the disruption of the blood supply to the femoral head, leading to the apoptosis and necrosis of bone cells and subsequent joint collapse. Total hip arthroplasty is not optimal since most patients are young. Multiple risk factors contribute to osteonecrosis, including glucocorticoid (GC) usage, excessive alcohol intake, hypercholesterolemia, and smoking. Continuous stimulation by many variables causes a chronic inflammatory milieu, with clinical repercussions including endothelial dysfunction, leading to thrombosis, coagulopathy, and poor angiogenesis. Immune cells are the primary regulators of inflammation. Innate and adaptive immune cells interact with endothelial cells to hinder the regeneration and repair of bone lesions. An in-depth examination of the pathological drivers of ONFH reveals that endothelial dysfunction may be a major cause of osteonecrosis. Understanding the involvement of endothelial dysfunction in the chronic inflammation of osteonecrosis could aid in the development of possible therapies. This review summarizes the role of endothelial cells in osteonecrosis and further explains the pathophysiological mechanism of endothelial dysfunction in this disease from the perspective of inflammation to provide new ideas for the treatment of osteonecrosis.
]]>Biomedicines doi: 10.3390/biomedicines12030663
Authors: Jessica M. Livingston Tina T. Lee Tom Enbar Emerson Daniele Clara M. Phillips Alexandra Krassikova K. W. Annie Bang Ines Kortebi Brennan W. Donville Omadyor S. Ibragimov Nadia Sachewsky Daniela Lozano Casasbuenas Arman Olfat Cindi M. Morshead
Stroke is the leading cause of adult disability worldwide. The majority of stroke survivors are left with devastating functional impairments for which few treatment options exist. Recently, a number of studies have used ectopic expression of transcription factors that direct neuronal cell fate with the intention of converting astrocytes to neurons in various models of brain injury and disease. While there have been reports that question whether astrocyte-to-neuron conversion occurs in vivo, here, we have asked if ectopic expression of the transcription factor Neurod1 is sufficient to promote improved functional outcomes when delivered in the subacute phase following endothelin-1-induced sensory–motor cortex stroke. We used an adeno-associated virus to deliver Neurod1 from the short GFAP promoter and demonstrated improved functional outcomes as early as 28 days post-stroke and persisting to at least 63 days post-stroke. Using Cre-based cell fate tracking, we showed that functional recovery correlated with the expression of neuronal markers in transduced cells by 28 days post-stroke. By 63 days post-stroke, the reporter-expressing cells comprised ~20% of all the neurons in the perilesional cortex and expressed markers of cortical neuron subtypes. Overall, our findings indicate that ectopic expression of Neurod1 in the stroke-injured brain is sufficient to enhance neural repair.
]]>Biomedicines doi: 10.3390/biomedicines12030662
Authors: Wiktoria Smyła-Gruca Wioletta Szczurek-Wasilewicz Michał Skrzypek Andrzej Karmański Ewa Romuk Michał Jurkiewicz Mariusz Gąsior Bożena Szyguła-Jurkiewicz
The role of oxidative/antioxidative system imbalances in advanced heart failure (HF) has not been fully investigated. The aim of this study was to identify factors associated with one-year mortality in patients with advanced HF, with particular emphasis on oxidative/antioxidative balance parameters. We analyzed 85 heart transplant candidates who were hospitalized at our institution for right heart catheterization. Ten milliliters of coronary sinus blood was collected to measure oxidative/antioxidative markers. The median age was 58 (50–62) years, and 90.6% of them were male. The one-year mortality rate was 40%. Multivariable logistic regression analysis revealed that ceruloplasmin (OR = 1.342 [1.019–1.770], p = 0.0363; per unit decrease), catalase (OR = 1.053 [1.014–1.093], p = 0.0076; per unit decrease), and creatinine (OR = 1.071 [1.002–1.144], p = 0.0422; per unit increase) were independently associated with one-year mortality. Ceruloplasmin, catalase, and creatinine had areas under the curve of 0.9296 [0.8738–0.9855], 0.9666 [0.9360–0.9971], and 0.7682 [0.6607–0.8756], respectively. Lower ceruloplasmin and catalase in the coronary sinus, as well as higher creatinine in peripheral blood, are independently associated with one-year mortality in patients with advanced HF. Catalase and ceruloplasmin have excellent prognostic power, and creatinine has acceptable prognostic power, allowing the distinction of one-year survivors from nonsurvivors.
]]>Biomedicines doi: 10.3390/biomedicines12030661
Authors: Youzhi Wang Ning Wu Junbo Li Diansheng Zhou Jiaming Liang Qian Cao Zhaokai Guan Yangyang Xu Ning Jiang
The emergence of castration-resistant prostate cancer (CRPC) following androgen deprivation therapy (ADT) is associated with increased malignancy and limited treatment options. This study aims to investigate potential connections between immune cell infiltration and inflammatory cytokines with the YAP1/AR/PSA axis by exploring their interactions with autophagy. Our research reveals heightened levels of Yes-associated protein 1 (YAP1) expression in CRPC tissues compared with tissues from androgen-dependent prostate cancer (ADPC) and benign prostate hyperplasia (BPH). Additionally, a correlation was observed between YAP1 and PSA expressions in CRPC tissues, suggesting that YAP1 may exert a regulatory influence on PSA expression within CRPC. Enhanced YAP1 expression in C4-2 cells resulted in the upregulation of androgen receptor (AR) nuclear translocation and intracellular prostate-specific antigen (PSA) levels. Conversely, the suppression of YAP1 led to a decrease in PSA expression, suggesting that YAP1 may positively regulate the PSA in castration-resistant prostate cancer (CRPC) by facilitating AR nuclear import. The modulation of the autophagy activity exerts a significant impact on the expression levels of YAP1, the AR, and the PSA. Moreover, recent advancements in immunity and inflammation studies present promising avenues for potential therapies targeting prostate cancer (PC).
]]>Biomedicines doi: 10.3390/biomedicines12030660
Authors: Zong-Ping Weng Shen-Kai Hsu Hui-Min David Wang Kuo-Jen Chen Po-Yen Lee Chien-Chih Chiu Kai-Chun Cheng
Esophageal cancer (EC) is one of the most aggressive gastrointestinal cancers. Despite improvements in therapies, the survival rate of patients with EC remains low. Metastasis accounts for up to 90% of cancer-related deaths, and resistance to anti-neoplastic therapeutics is also a main cause of poor survival. Thus, metastasis and drug resistance are undoubtedly the two main challenges in cancer treatment. Among the different categories of noncoding RNAs, lncRNAs have historically drawn less attention. However, lncRNAs have gradually become a research hotspot, and increasing research has demonstrated that lncRNAs participate in the tumorigenesis of multiple types of cancer, including EC. Long noncoding RNAs (lncRNAs) are RNA transcripts longer than 200 nucleotides in length that play important roles in epigenetics, transcription regulation, and posttranscriptional processing. In this review, we elucidated the role of lncRNAs in the metastasis and drug resistance of EC and discussed their potential clinical applications and related limitations. With a better understanding of the underlying mechanisms of lncRNAs, we can identify therapeutic targets for EC in the future.
]]>Biomedicines doi: 10.3390/biomedicines12030659
Authors: Georgi P. Georgiev Yordan Yordanov Lyubomir Gaydarski Richard Shane Tubbs Łukasz Olewnik Nicol Zielinska Maria Piagkou Julian Ananiev Iva N. Dimitrova Svetoslav A. Slavchev Ivan Terziev Athikhun Suwannakhan Boycho Landzhov
The human knee is a complex joint that comprises several ligaments, including the medial collateral ligament (MCL). The MCL provides stability to the knee and helps prevent its excessive inward movement. The MCL also has a thin layer of connective tissue known as the epiligament (EL), which adheres to the ligament. This unique feature has drawn attention in the field of ligament healing research, as it may have implications for the recovery process of MCL injuries. According to the EL theory, ligament regeneration relies heavily on the provision of cells, blood vessels, and molecules. The present study sought to compare the expression of vascular endothelial growth factor (VEGF), CD34, and α-smooth muscle actin (α-SMA) in healthy knees’ proximal and distal MCL segments to better understand how these proteins affect ligament healing. By improving the EL theory, the current results could lead to more effective treatments for ligament injury. To conduct the present analysis, monoclonal antibodies were used against CD34, α-SMA, and VEGF to examine samples from 12 fresh knee joints’ midsubstance MCLs. We identified a higher cell density in the EL than in the ligament connective tissue, with higher cell counts in the distal than in the proximal EL part. CD34 immunostaining was weak or absent in blood vessels and the EL, while α-SMA immunostaining was strongest in smooth muscle cells and the EL superficial layer. VEGF expression was mainly in the blood vessels’ tunica media. The distal part showed more SMA-positive microscopy fields and higher cell density than the proximal part (4735 vs. 2680 cells/mm2). Our study identified CD34, α-SMA, and VEGF expression in the MCL EL, highlighting their critical role in ligament healing. Differences in α-SMA expression and cell numbers between the ligament’s proximal and distal parts may explain different healing capacities, supporting the validity of the EL theory in ligament recovery.
]]>Biomedicines doi: 10.3390/biomedicines12030658
Authors: Francesca Maria Orlandella Esther Imperlini Katia Pane Neila Luciano Mariantonia Braile Anna Elisa De Stefano Paola Lucia Chiara Iervolino Alessandro Ruocco Stefania Orrù Monica Franzese Giuliana Salvatore
During tumorigenesis, miRNAs with unbalanced expression profiles can increase the threat of disease progression. Here, we focus on the role of miR-331-5p in the pathogenesis of thyroid cancer (TC). In vitro studies were conducted using TC cell lines after the forced expression and silencing of miR-331-5p. Cell proliferation and viability were analyzed via cell counts and colorimetric assays. Cell motility was analyzed via wound healing assays, Transwell migration and invasion assays, and Matrigel Matrix assays. The putative targets of miR-331-5p were unveiled via label-free proteomic screening and then verified using Western blot and luciferase assays. Expression studies were conducted by interrogating The Cancer Genome Atlas (TCGA). We found that ectopic miR-331-5p expression reduces TC cell motility, while miR-331-5p silencing induces the opposite phenotype. Proteomic screening revealed eight putative downregulated targets of miR-331-5p, among which BID was confirmed as a direct target. TCGA data showed the downregulation of miR-331-5p and the upregulation of BID in TC tissues. In summary, deregulation of the miR-331-5p/BID axis could enhance the aggressiveness of TC cell lines, providing new insights into the mechanisms of the progression of this disease and suggesting a potential role of the component factors as possible biomarkers in TC tissues.
]]>Biomedicines doi: 10.3390/biomedicines12030657
Authors: Merita Rroji Goce Spasovski
Diabetic kidney disease (DKD) is a substantial complication of type 2 diabetes (T2D), presenting challenges in chronic kidney disease (CKD) management. In addition to traditional and recent therapies, including angiotensin, converting enzyme (ACE) inhibitors, angiotensin receptor blockers, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and mineralocorticoid receptor antagonists, the evolution of antihyperglycemic treatments has introduced a promising agent, glucagon-like peptide-1 receptor agonist (GLP-1RA) for the management of DKD. GLP-1RAs enhance insulin release and reduce glucagon release, offering a novel approach to DKD management. This review analyzes the molecular pathways through which GLP1-RAs confer renal protection in T2D and DKD, which are complex and multifaceted. They include modulation of renal hemodynamics, antioxidative and anti-inflammatory actions, metabolic regulation, and direct cellular effects. These mechanisms highlight GLP1-RA’s potential as a therapeutic option for glycemic control and direct or indirect renal function protection in diabetic patients, emphasizing the potentiality of GLP-1RAs for dual therapy, with cardiovascular and renal protection as a holistic approach. Clinical evidence supports GLP-1RAs in reducing albuminuria and enhancing kidney outcomes, highlighting their value in a comprehensive DKD management strategy.
]]>Biomedicines doi: 10.3390/biomedicines12030656
Authors: Francesco Piccirillo Sara Mastroberardino Vincenzo Nafisio Matteo Fiorentino Andrea Segreti Annunziata Nusca Gian Paolo Ussia Francesco Grigioni
Myocarditis is a polymorphic and potentially life-threatening disease characterized by a large variability in clinical presentation and prognosis. Within the broad spectrum of etiology, eosinophilic myocarditis represents a rare condition characterized by eosinophilic infiltration of the myocardium, usually associated with peripheral eosinophilia. Albeit uncommon, eosinophilic myocarditis could be potentially life-threatening, ranging from mild asymptomatic disease to multifocal widespread infiltrates associated with myocardial necrosis, thrombotic complications, and endomyocardial fibrosis. Moreover, it could progress to dilated cardiomyopathy, resulting in a poor prognosis. The leading causes of eosinophilic myocarditis are hypersensitivity reactions, eosinophilic granulomatosis with polyangiitis, cancer, hyper-eosinophilic syndrome variants, and infections. A thorough evaluation and accurate diagnosis are crucial to identifying the underlying cause and defining the appropriate therapeutic strategy. On these bases, this comprehensive review aims to summarize the current knowledge on eosinophilic myocarditis, providing a schematic and practical approach to diagnosing, evaluating, and treating eosinophilic myocarditis.
]]>Biomedicines doi: 10.3390/biomedicines12030655
Authors: Heng-Yuan Hsu Jui-Hsiang Tang Song-Fong Huang Chun-Wei Huang Sey-En Lin Shu-Wei Huang Chao-Wei Lee Tsung-Han Wu Ming-Chin Yu
Background: The perioperative outcomes of a partial hepatectomy for hepatocellular carcinoma (HCC) have improved. However, high recurrence rates after a curative hepatectomy for HCC is still an issue. This study aimed to analyze the difference between various recurrence patterns. Methods: We retrospectively reviewed 754 patients with HCC who underwent a curative hepatectomy between January 2012 and March 2021. Patients with recurrent events were categorized into three types: regional recurrence (type I), multiple intrahepatic recurrence (type II), or presence of any distant metastasis (type III). Results: The median follow-up period was 51.2 months. Regarding recurrence, 375 (49.7%) patients developed recurrence, with 244 (32.4%), 51 (6.8%), and 80 (10.6%) patients having type I, II, and III recurrence, respectively. Type III recurrence appeared to be more common in male patients and those with major liver resection, vascular invasion, a large tumor size (>5 cm), a higher tumor grade, and higher levels of AST and AFP (p < 0.05). Patients who had distant metastasis at recurrence had the shortest recurrence time and the worst overall survival (p < 0.001 and p < 0.001). Conclusions: our study demonstrated that recurrence with distant metastasis occurred earliest and had the worst outcome compared to regional or multiple intrahepatic recurrences.
]]>Biomedicines doi: 10.3390/biomedicines12030654
Authors: Katarzyna Zych-Krekora Oskar Sylwestrzak Michał Krekora Przemysław Oszukowski Mariusz Grzesiak
Developments in medicine and biology in recent decades have led to a significant increase in our knowledge of the complex interactions between the microbiota and human health. In the context of perinatal medicine and neonatology, particular attention is being paid to the potential impact of the maternal microbiota on fetal development. Among the many aspects of this relationship, the question of the impact of dysbiosis on the development of fetal heart defects is an important one. In this article, we present an analysis of recent research and scientific evidence on the relationship between a pregnant woman’s microbiota and the development of fetal heart defects. We also discuss potential intervention strategies, including the role of probiotics and diet in optimising the maternal microbiota.
]]>Biomedicines doi: 10.3390/biomedicines12030652
Authors: Kazue Takai
TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis of bone marrow/renal dysfunction, organomegaly) syndrome is a systemic inflammatory disorder of unknown etiology. It has been recognized as a subtype of idiopathic multicentric Castleman disease (iMCD), and the international diagnostic criteria for iMCD-TAFRO require a lymph node histopathology consistent with iMCD. Furthermore, TAFRO syndrome is defined as a heterogeneous clinical entity caused by underlying diseases such as malignancy, autoimmune diseases, or infections. However, the cases that led to the proposal of TAFRO syndrome lacked recognizable lymphadenopathy and were inconsistent with any other diseases, despite vigorous efforts in differential diagnosis. Irrespective of the presence or absence of Castleman disease (CD)-like histology, TAFRO syndrome exhibits homogeneous clinical, laboratory, and prognostic features, setting it apart from iMCD without TAFRO syndrome. Defining iMCD-TAFRO apart from TAFRO syndrome is deemed meaningless and confusing. MCD is a heterogeneous lymphoproliferative disorder consisting of several subtypes with different pathogenesis, clinical manifestations, and histological features. Typical MCD in Japan, characterized by the histology of plasma cell type and marked polyclonal hypergammaglobulinemia, is identical to idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (IPL). Although IPL is classified into iMCD-NOS (not otherwise specified), it should be recognized as a distinct clinicopathological entity. Furthermore, we propose to separate TAFRO syndrome from the MCD category as a defined disorder.
]]>Biomedicines doi: 10.3390/biomedicines12030653
Authors: Andrea Etrusco Mislav Mikuš Antonio D’Amato Fabio Barra Petar Planinić Trpimir Goluža Giovanni Buzzaccarini Jelena Marušić Mara Tešanović Antonio Simone Laganà
Background: The purpose of this narrative review is to describe the mechanisms that are responsible for the development of infertility and PCOS, with a focus on the role of obesity, insulin sensitivity and treatment with metformin and GLP-1s. Methods: The relevant publications were identified after systematic queries of the following sources: PubMed, Google Scholar, Web of Science, and publishers’ databases, complemented by a cross-check of the reference lists. We used a combination of the search terms “polycystic ovary syndrome”, “obesity” and “insulin resistance” with “metformin”, “exenatide”, “liraglutide”, “semaglutide”, “orlistat” and terms relevant to the topic of each paragraph (e.g., “pathophysiology”, “metabolism”, “infertility”, “treatment”). Results: All articles describing the mechanisms responsible for the development of infertility and PCOS, with a focus on the role of obesity, insulin sensitivity and treatment with metformin and GLP-1s, were considered for this review. Conclusions: The existing research on GLP-1 receptor agonists (GLP-1RAs) has not conclusively established a specific therapeutic use for these drugs. Additionally, the efficacy of the newer generation of GLP-1RAs, particularly in terms of dosage and duration of exposure, warrants more extensive research. Understanding the optimal dosing and treatment duration could significantly enhance the therapeutic use of GLP-1RAs in managing PCOS and its associated conditions.
]]>Biomedicines doi: 10.3390/biomedicines12030649
Authors: Christine Chandran Mithun Santra Elizabeth Rubin Moira L. Geary Gary Hin-Fai Yam
The cornea is a transparent and vitally multifaceted component of the eye, playing a pivotal role in vision and ocular health. It has primary refractive and protective functions. Typical corneal dysfunctions include opacities and deformities that result from injuries, infections, or other medical conditions. These can significantly impair vision. The conventional challenges in managing corneal ailments include the limited regenerative capacity (except corneal epithelium), immune response after donor tissue transplantation, a risk of long-term graft rejection, and the global shortage of transplantable donor materials. This review delves into the intricate composition of the cornea, the landscape of corneal regeneration, and the multifaceted repercussions of scar-related pathologies. It will elucidate the etiology and types of dysfunctions, assess current treatments and their limitations, and explore the potential of regenerative therapy that has emerged in both in vivo and clinical trials. This review will shed light on existing gaps in corneal disorder management and discuss the feasibility and challenges of advancing regenerative therapies for corneal stromal scarring.
]]>Biomedicines doi: 10.3390/biomedicines12030651
Authors: Nozomi Takahashi Miyuki Harada Mayuko Kanatani Osamu Wada-Hiraike Yasushi Hirota Yutaka Osuga
It is unclear whether clinical background differs between endometriosis in adolescent patients with obstructive Müllerian anomalies and those without anomalies. The aim of the study is to identify the difference in clinical characteristics of endometriosis in patients with or without obstructive Müllerian anomalies. The study involved 12 patients aged under 24 years old who underwent primary surgery for obstructive Müllerian anomalies and 31 patients aged under 24 years old who underwent surgery for ovarian endometrioma. A total of 6 out of 12 cases with obstructive Müllerian anomalies developed endometriosis (4 Herlyn–Werner–Wunderlich syndrome, 2 non-communicating functional uterine horn, 2 cervical aplasia). The age at surgery was significantly younger in endometriosis with obstructive Müllerian anomalies, compared with those without obstructive Müllerian anomalies (17.8 ± 4.4 vs. 23.1 ± 1.3, p = 0.0007). The rate of endometrioma was 50.0% and the rate of hydrosalpinx was significantly higher (66.7% vs. 0%, p = 0.0002) in the group of obstructive Müllerian anomalies. The recurrence rate of endometriosis was 20.0% in the group of anomalies and 25.9% in the group of those without anomalies. Adolescent patients with obstructive Müllerian anomalies more easily developed endometriosis and co-occurred with higher rate of hematosalipinx.
]]>Biomedicines doi: 10.3390/biomedicines12030650
Authors: Anastasia I. Palamarchuk Elena I. Kovalenko Maria A. Streltsova
The NK cell exhaustion state evolving during extensive and prolonged cultivation is still one of the limitations of NK cell approaches. In this research, we transduced NK cells with the hTERT and iCasp9 genes. hTERT overexpression can prevent the functional exhaustion of NK cells during long-term cultivation, but, still, the therapeutic use of such cells is unsafe without irradiation. To overcome this obstacle, we additionally transduced NK cells with the iCasp9 transgene that enables the rapid elimination of modified cells. We compared the proliferative and functional activities of the hTERT- and/or iCasp9-modified NK cells, determined their exhaustion state and monitored the levels of EOMES and T-BET, the main NK cell transcription factors. The hTERT and iCasp9 genes were shown to affect the EOMES and T-BET levels differently in the NK cells. The EOMES+T-BET+ phenotype characterized the functionally active NK cells during two months of culture upon stimulation with IL2 and K562-mbIL21 feeder cells, which induced the greatest expansion rates of the NK cells, independently of the transgene type. On the other hand, under cytokine stimulation, the hTERT-iCasp9-NK cells displayed improved proliferation over NK cells modified with iCasp9 alone and showed an increased proliferation rate compared to the untransduced NK cells under stimulation with IL2 and IL15, which was accompanied by reduced immune checkpoint molecule expression. The individual changes in the EOMES and T-BET levels strictly corresponded to the NK cell functional activity, the surface levels of activating and inhibitory receptors along with the expansion rate and expression levels of pro-survival and pro-apoptotic genes.
]]>Biomedicines doi: 10.3390/biomedicines12030648
Authors: Lajos Gergely Miklos Udvardy Arpad Illes
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. The disease is very heterogeneous, with distinct genetic alterations in subtypes. The WHO 2022 5th edition classification identifies several minor groups of large B-cell lymphoma where the pathogenetic role of viruses (like EBV and HHV-8) is identified. Still, most cases fall into the group of DLBCL not otherwise specified (NOS). No review focuses only on this specific lymphoma type in the literature. The pathogenesis of this entity is still not fully understood, but several viruses and bacteria may have a role in the development of the disease. The authors review critical pathogenetic events in the development of DLBCL (NOS) and summarize the data available on several pathogenetic viruses and bacteria that have a proven or may have a potential role in the development of this lymphoma type. The possible role of B-cell receptor signaling in the microenvironment is also discussed. The causative role of the Epstein–Barr virus (EBV), human herpesvirus-8 (HHV-8), Hepatitis C virus (HCV), human immunodeficiency virus (HIV), Hepatitis B virus (HBV), and other viruses are explored. Bacterial infections, such as Helicobacter pylori, Campylobacter jejuni, Chlamydia psittaci, Borrelia burgdorferi, and other bacteria, are also reviewed.
]]>Biomedicines doi: 10.3390/biomedicines12030647
Authors: Mariana Pereira Nuno Vale
This research explores the therapeutic efficacy of Darunavir (DRV), Rilpivirine (RPV), and Etravirine (ETV) against UM-UC-5 bladder cancer cells, addressing the critical need for innovative treatments in bladder cancer research. Through a comprehensive assessment of their individual and combined effects across diverse time intervals, ETV emerges as the most potent drug, with a lowest IC50 of 5.9 µM, closely followed by RPV (lowest IC50 of 9.6 µM), while DRV exhibits the least effectiveness (lowest IC50 of 25.6 µM). Notably, a significant synergistic effect is evident in the ETV and RPV combination, especially at 48 and 72 h for low concentrations. Synergies are also observed with ETV and DRV, albeit to a lesser extent and primarily at 48 h. Conversely, the DRV and RPV combination yields minimal effects, predominantly additive in nature. In summary, this pre-clinical investigation underscores the promising therapeutic potential of ETV and RPV, both as standalone treatments and in combination, hinting at repurposing opportunities in bladder cancer therapy, which could give a new treatment method for this disease that is faster and without as severe side effects as anticancer drugs. These findings represent a substantial stride in advancing personalized medicine within cancer research and will be further scrutinized in forthcoming studies.
]]>Biomedicines doi: 10.3390/biomedicines12030646
Authors: Attila Szvetnik Vilmos Tubak
Therapeutic recombinant proteins are powerful tools used for the treatment of many detrimental diseases such as diabetes, cancer, multiple sclerosis, rheumatoid arthritis, hepatitis, and many more. Their importance in disease therapy is growing over small molecule drugs because of their advantages like specificity and reduced side effects. However, the large-scale production of certain recombinant proteins is still challenging despite impressive advancements in biomanufacturing. The complement cascade is considered a rich source of drug targets and natural regulator proteins with great therapeutic potential. However, the versatility of such proteins has been hampered by low production rates. The recent discoveries highlighted here may bring definite improvement in the large-scale recombinant production of complement inhibitor proteins or other difficult-to-express proteins in mammalian cell lines.
]]>Biomedicines doi: 10.3390/biomedicines12030645
Authors: Vasile Valeriu Lupu Roxana Mihaela Bratu Laura Mihaela Trandafir Laura Bozomitu Gabriela Paduraru Nicoleta Gimiga Gabriela Ghiga Lorenza Forna Ileana Ioniuc Florin Dumitru Petrariu Bogdan Puha Ancuta Lupu
The gut microbiota is emerging as an important contributor to the homeostasis of the human body through its involvement in nutrition and metabolism, protection against pathogens, and the development and modulation of the immune system. It has therefore become an important research topic in recent decades. Although the association between intestinal dysbiosis and numerous digestive pathologies has been thoroughly researched, its involvement in pancreatic diseases constitutes a novelty in the specialized literature. In recent years, growing evidence has pointed to the critical involvement of the pancreas in regulating the intestinal microbiota, as well as the impact of the intestinal microbiota on pancreatic physiology, which implies the existence of a bidirectional connection known as the “gut–pancreas axis”. It is theorized that any change at either of these levels triggers a response in the other component, hence leading to the evolution of pancreatitis. However, there are not enough data to determine whether gut dysbiosis is an underlying cause or a result of pancreatitis; therefore, more research is needed in this area. The purpose of this narrative review is to highlight the role of gut dysbiosis in the pathogenesis of acute and chronic pancreatitis, its evolution, and the prospect of employing the microbiota as a therapeutic intervention for pancreatitis.
]]>Biomedicines doi: 10.3390/biomedicines12030644
Authors: Martin Kondža Ivica Brizić Stela Jokić
Flavonoids, a diverse group of polyphenolic compounds found abundantly in fruits, vegetables, and beverages like tea and wine, offer a plethora of health benefits. However, they have a potential interaction with drug metabolism, particularly through the inhibition of the cytochrome P450 3A4 enzyme, the most versatile and abundant enzyme in the liver. CYP3A4 is responsible for metabolizing approximately 50% of clinically prescribed drugs across diverse therapeutic classes, so these interactions have raised concerns about potential adverse effects. This review delves into the scientific evidence surrounding flavonoid-mediated CYP3A4 inhibition, exploring the inhibitory potential of investigated flavonoids and future implications. Kusehnol I, chrysin, leachianone A, and sophoraflavone G showed the largest inhibitory potentials and lowest IC50 values. While the clinical significance of flavonoid-mediated CYP3A4 inhibition in dietary contexts is generally considered low due to moderate intake and complex interactions, it poses a potential concern for individuals consuming high doses of flavonoid supplements or concurrently taking medications metabolized by CYP3A4. This can lead to increased drug exposure, potentially triggering adverse reactions or reduced efficacy.
]]>Biomedicines doi: 10.3390/biomedicines12030643
Authors: Andrew R. Stevens Antonio Belli Zubair Ahmed
Traumatic injury to the brain and spinal cord (neurotrauma) is a common event across populations and often causes profound and irreversible disability. Pathophysiological responses to trauma exacerbate the damage of an index injury, propagating the loss of function that the central nervous system (CNS) cannot repair after the initial event is resolved. The way in which function is lost after injury is the consequence of a complex array of mechanisms that continue in the chronic phase post-injury to prevent effective neural repair. This review summarises the events after traumatic brain injury (TBI) and spinal cord injury (SCI), comprising a description of current clinical management strategies, a summary of known cellular and molecular mechanisms of secondary damage and their role in the prevention of repair. A discussion of current and emerging approaches to promote neuroregeneration after CNS injury is presented. The barriers to promoting repair after neurotrauma are across pathways and cell types and occur on a molecular and system level. This presents a challenge to traditional molecular pharmacological approaches to targeting single molecular pathways. It is suggested that novel approaches targeting multiple mechanisms or using combinatorial therapies may yield the sought-after recovery for future patients.
]]>Biomedicines doi: 10.3390/biomedicines12030642
Authors: Ilse Roodink Maartje van Erp Andra Li Sheila Potter Sander M. J. van Duijnhoven Milou Smits Arthur J. Kuipers Bert Kazemier Bob Berkeveld Ellen van Geffen Britte S. de Vries Danielle Rijbroek Bianca Boers Sanne Meurs Wieger Hemrika Alexandra Thom Barry N. Duplantis Roland A. Romijn Jeremy S. Houser Jennifer L. Bath Yasmina N. Abdiche
Therapeutic antibodies (Abs) which act on a broader range of epitopes may provide more durable protection against the genetic drift of a target, typical of viruses or tumors. When these Abs exist concurrently on the targeted antigen, several mechanisms of action (MoAs) can be engaged, boosting therapeutic potency. This study selected combinations of four and five Abs with non- or partially overlapping epitopes to the SARS-CoV-2 spike glycoprotein, on or outside the crucial receptor binding domain (RBD), to offer resilience to emerging variants and trigger multiple MoAs. The combinations were derived from a pool of unique-sequence scFv Ab fragments retrieved from two SARS-CoV-2-naïve human phage display libraries. Following recombinant expression to full-length human IgG1 candidates, a biolayer interferometric analysis mapped epitopes to bins and confirmed that up to four Abs from across the bins can exist simultaneously on the spike glycoprotein trimer. Not all the bins of Abs interfered with the spike protein binding to angiotensin converting enzyme 2 (ACE2) in competitive binding assays, nor neutralized the pseudovirus or authentic virus in vitro, but when combined in vivo, their inclusion resulted in a much stronger viral clearance in the lungs of intranasally challenged hamsters, compared to that of those treated with mono ACE2 blockers. In addition, the Ab mixtures activated in vitro reporter cells expressing Fc-gamma receptors (FcγRs) involved in antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). The best four-Ab combination neutralized seventeen variants of concern from Wuhan-Hu1 to Omicron BA.4/BA.5 in vitro.
]]>Biomedicines doi: 10.3390/biomedicines12030640
Authors: Kamyar Zahedi Sharon Barone Marybeth Brooks Tracy Murray Stewart Jackson R. Foley Ashley Nwafor Robert A. Casero Manoocher Soleimani
Cisplatin, a chemotherapeutic agent, can cause nephrotoxic and ototoxic injuries. Using a mouse model of repeated low dose cisplatin (RLDC), we compared the kidneys of cisplatin- and vehicle-treated mice on days 3 (early injury phase) and 35 (late injury/recovery phase) after the final treatment. RNA-seq analyses revealed increases in the expression of markers of kidney injury (e.g., lipocalin 2 and kidney injury molecule 1) and fibrosis (e.g., collagen 1, fibronectin, and vimentin 1) in RLDC mice. In addition, we observed increased expression of polyamine catabolic enzymes (spermidine/spermine N1-acetyltransferase, Sat1, and spermine oxidase, Smox) and decreased expression of ornithine decarboxylase (Odc1), a rate-limiting enzyme in polyamine synthesis in mice subjected to RLDC. Upon confirmation of the RNA-seq results, we tested the hypothesis that enhanced polyamine catabolism contributes to the onset of renal injury and development of fibrosis. To test our hypothesis, we compared the severity of RLDC-induced renal injury and fibrosis in wildtype (WT), Sat1-KO, and Smox-KO mice. Our results suggest that the ablation of polyamine catabolic enzymes reduces the severity of renal injury and that modulation of the activity of these enzymes may protect against kidney damage and fibrosis caused by cisplatin treatment.
]]>Biomedicines doi: 10.3390/biomedicines12030641
Authors: Christiane Hartmann Marie Anskat Marc Ehrlich Jared Sterneckert Arun Pal Andreas Hermann
Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by the progressive loss of neurons mainly in the frontal and temporal lobes of the brain. Mutations (e.g., V337M, N297K) in the microtubule-associated protein TAU (MAPT) are responsible 5–20% of familial FTD cases and have been associated with defects in organelle trafficking that plays a critical role in the proper function of cells, including transport of essential molecules and degradation of waste products. Due to the critical role of TAU mutations in microtubule stabilization and organelle transportation, it is of great interest to study these molecular mechanisms to develop effective therapeutic strategies. Therefore, herein, we analyzed mitochondrial and lysosomal trafficking in disease-specific spinal motor neurons by using live cell imaging in undirected (uncompartmentalized) and directed (compartmentalized) cell culture systems. While V337M neurons only expressed 3R TAU, the N297K mutant neurons expressed both 3R and 4R TAU. Axonal trafficking was affected differentially in V337M and N297 MAPT mutated neurons. These findings suggest that the MAPT mutations V337M and N297K impaired axon physiology differentially, which highlights the need for mutation- and/or 3R/4R TAU-specific therapeutic approaches.
]]>Biomedicines doi: 10.3390/biomedicines12030639
Authors: Mihai Lazar Mihai Sandulescu Ecaterina Constanta Barbu Cristina Emilia Chitu-Tisu Darie Ioan Andreescu Andreea Nicoleta Anton Teodora Maria Erculescu Alexandru Mihai Petre George Theodor Duca Vladimir Simion Isabela Felicia Padiu Cosmina Georgiana Pacurar Ruxandra Rosca Teodor Mihai Simian Constantin Adrian Oprea Daniela Adriana Ion
SARS-CoV-2 infection is a significant health concern that needs to be addressed not only during the initial phase of infection but also after hospitalization. This is the consequence of the various pathologies associated with long COVID-19, which are still being studied and researched. Lung fibrosis is an important complication after COVID-19, found in up to 71% of patients after discharge. Our research is based on scientific articles indexed in PubMed; in the selection process, we used the following keywords: “lung fibrosis”, “fibrosis mediators”, “fibrosis predictors”, “COVID-19”, “SARS-CoV-2 infection”, and “long COVID-19”. In this narrative review, we aimed to discuss the current understanding of the mechanisms of initiation and progression of post-COVID-19 lung fibrosis (PC-19-LF) and the risk factors for its occurrence. The pathogenesis of pulmonary fibrosis involves various mediators such as TGF-β, legumain, osteopontin, IL-4, IL-6, IL-13, IL-17, TNF-α, Gal-1, Gal-3, PDGF, and FGFR-1. The key cellular effectors involved in COVID-19 lung fibrosis are macrophages, epithelial alveolar cells, neutrophils, and fibroblasts. The main fibrosis pathways in SARS-CoV-2 infection include hypoxemia-induced fibrosis, macrophage-induced fibrosis, and viral-fibroblast interaction-induced fibrosis.
]]>Biomedicines doi: 10.3390/biomedicines12030638
Authors: Telma de Sousa Carolina Sabença Miguel Ribeiro Mario Pino-Hurtado Carmen Torres Michel Hébraud Olimpia Alves Sara Sousa Eliana Costa Gilberto Igrejas Patrícia Poeta
Pseudomonas aeruginosa and Klebsiella pneumoniae are notorious for their resistance to antibiotics and propensity for biofilm formation, posing significant threats to human health. Epsilon-poly-L-lysine (ε-PL) emerges as a naturally occurring antimicrobial poly(amino acid), which positions it as a prospective agent for addressing challenges linked to multidrug resistance. ε-PL symbolizes a promising avenue in the pursuit of efficacious therapeutic strategies and warrants earnest consideration within the realm of clinical treatment. Thus, our objective was to determine the antibiotic susceptibility profiles of 38 selected P. aeruginosa and ESBL-producing K. pneumoniae clinical isolates and determine the ability of ε-PL to inhibit biofilm formation. After PCR analysis, detection of genes related to β-lactamases was observed among the selected isolates of P. aeruginosa [blaSPM (35.7%), blaKPC (35.7%), blaSHV (14.3%), blaCTX-M (14.3%), blaOXA (14.3%), blaTEM (7.1%), blaPER (7.1%), blaVIM (7.1%), and blaVIM-2 (7.1%)] and K. pneumoniae [blaCTX-M (91.7%), blaTEM (83.3%), blaKPC (16.7%), blaNDM (12.5%), and blaOXA (4.2%)]. The results of testing the activity of ε-PL against the clinical isolates showed relatively high minimum inhibitory concentrations (MICs) for the P. aeruginosa (range: 8–64 µg/mL) and K. pneumoniae isolates (range: 16–32 µg/mL). These results suggest the need for prior optimization of ε-PL concerning its viability as an alternative to antibiotics for treating infections caused by P. aeruginosa and K. pneumoniae of clinical origin. It is noteworthy that, in the context of a low antibiotic discovery rate, ε-PL could play a significant role in this quest, considering its low toxicity and the unlikely development of resistance. Upon exposure to ε-PL, P. aeruginosa and K. pneumoniae isolates exhibited a reduction in biofilm production, with ε-PL concentration showing an inverse relationship, particularly in isolates initially characterized as strong or moderate producers, indicating its potential as a natural antimicrobial agent with further research needed to elucidate optimal concentrations and application methods across different bacterial species. Further research is needed to optimize its use and explore its potential in various applications.
]]>Biomedicines doi: 10.3390/biomedicines12030637
Authors: Barbara Takács Anna Szilágyi Dániel Priksz Mariann Bombicz Adrienn Mónika Szabó Beáta Pelles-Taskó Ágnes Rusznyák Ádám Haimhoffer Rudolf Gesztelyi Zoltán Szilvássy Béla Juhász Balázs Varga
Retinal vascular diseases and consequential metabolic disturbances in the eye are major concerns for healthcare systems all around the world. BGP-15, a drug candidate small-molecule [O-(3-piperidino-2-hydroxy-1-propyl) nicotinic amidoxime dihydrochloride], has been formerly demonstrated by our workgroup to be retinoprotective both in the short and long term. Based on these results, the present study was performed to investigate the efficacy of BGP in an eyedrop formulation containing sulfobutylether-β-cyclodextrin (SBECD), which is a solubility enhancer as well. Electroretinographical evaluations were carried out and BGP was demonstrated to improve both scotopic and photopic retinal a- and b-waves, shorten their implicit times and restore oscillatory potentials after ischemia–reperfusion. It was also observed to counteract retinal thinning after ischemia–reperfusion in the eyes of Sprague Dawley rats. This small-molecule drug candidate is able to compensate for experimental global eye ischemia–reperfusion injury elicited by ligation of blood vessels in rats. We successfully demonstrated that BGP is able to exert its protective effects on the retina even if administered in the form of eyedrops.
]]>Biomedicines doi: 10.3390/biomedicines12030635
Authors: Viktoriya V. Antonova Denis N. Silachev Egor Y. Plotnikov Irina B. Pevzner Elmira I. Yakupova Mikhail V. Pisarev Ekaterina A. Boeva Zoya I. Tsokolaeva Maxim A. Lyubomudrov Igor V. Shumov Andrey V. Grechko Oleg A. Grebenchikov
This is the first in vivo study to investigate the neuroprotective effects of krypton on focal cerebral ischemia. The aim of the study was to analyze the effect of 2 h of inhalation of a krypton–oxygen mixture (Kr 70%/O2 30%) on the recovery of neurological functions and the degree of brain damage in rats after photoinduced ischemic stroke (PIS) and to investigate the possible mechanisms responsible for this neuroprotection. Experiments were performed on male Wistar rats weighing 250–300 g (n = 32). Animals were randomized into four groups. Two groups (n = 20) underwent photoinduced ischemic stroke, followed by 2 h of inhalation of krypton–oxygen mixture consisting of Kr 70%/O2 30% or a nitrogen–oxygen breathing mixture consisting of N2 70%/O2 30%, followed by neurological examinations on days 3 and 7. The other two groups (n = 12) received only gas mixtures of the same concentration and exposure duration as in those in the PIS groups, then Western blot analysis of the potential molecular mechanisms was performed. The results of the study show that treatment with the krypton–oxygen mixture consisting of Kr 70%/O2 30% improves the neurological status on day 7 of observation, reduces the lesion volume according to the MRI examination and the number of Iba-1- and caspase-3-positive cells in the damaged area, promotes the activation of neoangiogenesis (an increase in the von Willebrand factor), and reduces the penumbra area and the number of NeuN-positive cells in it on day 14 of observation. Inhalation of the krypton–oxygen mixture also significantly increases the levels of phosphorylated AKT kinase (protein kinase B) and glycogen synthase kinase 3b (pGSK3b) and promotes the expression of transcription factor Nrf2, which was accompanied by the lowered expression of transcription factor NFkB (p50). Thus, we showed pronounced neuroprotection induced by krypton inhalation after stroke and identified the signaling pathways that may be responsible for restoring neurological functions and reducing damage.
]]>Biomedicines doi: 10.3390/biomedicines12030636
Authors: Jelena Djordjevic Vesna Ignjatovic Vladimir Vukomanovic Katarina Vuleta Nevenka Ilic Zivana Slovic Marijana Stanojevic Pirkovic Olgica Mihaljevic
Bearing in mind that coronavirus disease (COVID-19) is associated with a wide range of laboratory abnormalities, the aim of this study was to examine the importance of determining the parameters of oxidative stress and antioxidant protection as well as markers of inflammation and hemostasis in hospitalized patients with COVID-19. The study population included 105 patients with severe COVID-19 and 65 healthy control subjects. The parameters of oxidative stress and the activity of enzymes of the antioxidant system were determined from the obtained samples using spectrophotometric methods. Standard laboratory methods were performed for the determination of the biochemical and hematological parameters. Patients with COVID-19 showed a significantly higher level of pro-oxidative parameters (hydrogen peroxide (H2O2) and the index of lipid peroxidation in the form of thiobarbituric acid-reactive substances (TBARSs)) and a significantly lower activity of the antioxidant system (catalase (CAT)). Patients with COVID-19 had significantly higher values of inflammation parameters (C-reactive protein (CRP), procalcitonin (PCT), ratio of the number of neutrophils to lymphocytes (NLR), and ratio of the number of platelets to lymphocytes (PLR)) and parameters of hemostasis (activated partial thromboplastin time (aPTT), prothrombin time (PT), D-dimer, fibrinogen) than the control healthy subjects. In addition, changes in hemostatic parameters correlated positively with inflammatory markers in the group of patients with COVID-19. The early determination of hemostasis parameters and the parameters of inflammation can help in the prediction of poor prognosis in COVID-19 patients.
]]>Biomedicines doi: 10.3390/biomedicines12030634
Authors: Anna Krzywonos-Zawadzka Agnieszka Olejnik Grzegorz Sawicki Iwona Bil-Lula
Background: The fact that during myocardial ischemia/reperfusion (I/R) injury, myosin light chain 1 (MLC1) and troponin I (TnI) are degraded by matrix metalloproteases activity has already been well established in both in vitro and ex vivo studies. However, I/R injury is a complex issue based on several overlapping mechanisms. Increased activity of myosin light chain kinase and nitric oxide synthase due to oxidative stress leads to post-translational modifications of MLC1, thus leading to the increased degradation of these proteins. Methods: Wistar rats were subjected to left anterior descending coronary artery occlusion. To measure the pharmacological effect of doxycycline, transthoracic echocardiography as well as biochemical tests, concentrations of TnI, LDH, MLC1, MMP-2 and MMP-9 were performed. Gelatinize activity and cytotoxicity level were also assessed; Results: I.p., administration of doxycycline before LAD occlusion surgery increased TnI and LDH content in the heart and decreased cytotoxicity. A reduction of MMP-2 and MMP-9 concentration and MMP-2 activity after administration of Doxy was also observed, as well as improvement in echocardiographic parameters just 7 days after surgery. Conclusions: Inhibition of MMPs by doxycycline, in vivo, may serve as a protective agent in future therapy.
]]>Biomedicines doi: 10.3390/biomedicines12030633
Authors: Maria J. Rodrigo Manuel Subías Alberto Montolío Teresa Martínez-Rincón Alba Aragón-Navas Irene Bravo-Osuna Luis E. Pablo Jose Cegoñino Rocío Herrero-Vanrell Elena Garcia-Martin Amaya Pérez del Palomar
Glaucoma is a multifactorial pathology involving the immune system. The subclinical immune response plays a homeostatic role in healthy situations, but in pathological situations, it produces imbalances. Optical coherence tomography detects immune cells in the vitreous as hyperreflective opacities and these are subsequently characterised by computational analysis. This study monitors the changes in immunity in the vitreous in two steroid-induced glaucoma (SIG) animal models created with drug delivery systems (microspheres loaded with dexamethasone and dexamethasone/fibronectin), comparing both sexes and healthy controls over six months. SIG eyes tended to present greater intensity and a higher number of vitreous opacities (p < 0.05), with dynamic fluctuations in the percentage of isolated cells (10 µm2), non-activated cells (10–50 µm2), activated cells (50–250 µm2) and cell complexes (>250 µm2). Both SIG models presented an anti-inflammatory profile, with non-activated cells being the largest population in this study. However, smaller opacities (isolated cells) seemed to be the first responder to noxa since they were the most rounded (recruitment), coinciding with peak intraocular pressure increase, and showed the highest mean Intensity (intracellular machinery), even in the contralateral eye, and a major change in orientation (motility). Studying the features of hyperreflective opacities in the vitreous using OCT could be a useful biomarker of glaucoma.
]]>Biomedicines doi: 10.3390/biomedicines12030632
Authors: Sara Osorio-Valencia Bisheng Zhou
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), present life-threatening conditions characterized by inflammation and endothelial injury, leading to increased vascular permeability and lung edema. Key players in the pathogenesis and resolution of ALI are macrophages (Mφs) and endothelial cells (ECs). The crosstalk between these two cell types has emerged as a significant focus for potential therapeutic interventions in ALI. This review provides a brief overview of the roles of Mφs and ECs and their interplay in ALI/ARDS. Moreover, it highlights the significance of investigating perivascular macrophages (PVMs) and immunomodulatory endothelial cells (IMECs) as crucial participants in the Mφ–EC crosstalk. This sheds light on the pathogenesis of ALI and paves the way for innovative treatment approaches.
]]>Biomedicines doi: 10.3390/biomedicines12030631
Authors: Carlos Nascimento Vasco Guerreiro-Pinto Seweryn Pawlak Ana Caulino-Rocha Laia Amat-Garcia Diana Cunha-Reis
Novelty detection, crucial to episodic memory formation, is impaired in epileptic patients with mesial temporal lobe resection. Mismatch novelty detection, that activates the hippocampal CA1 area in humans and is vital for memory reformulation and reconsolidation, is also impaired in patients with hippocampal lesions. In this work, we investigated the response to mismatch novelty, as occurs with the new location of known objects in a familiar environment, in the Li2+-pilocarpine rat model of TLE and its correlation with hippocampal monoaminergic markers. Animals showing spontaneous recurrent seizures (SRSs) for at least 4 weeks at the time of behavioural testing showed impaired spatial learning in the radial arm maze, as described. Concurrently, SRS rats displayed impaired exploratory responses to mismatch novelty, yet novel object recognition was not significantly affected in SRS rats. While the levels of serotonin and dopamine transporters were mildly decreased in hippocampal membranes from SRS rats, the levels on the norepinephrine transporter, tyrosine hydroxylase and dopamine-β-hydroxylase were enhanced, hinting for an augmentation, rather than an impairment in noradrenergic function in SRS animals. Altogether, this reveals that mismatch novelty detection is particularly affected by hippocampal damage associated to the Li2+-pilocarpine model of epilepsy 4–8 weeks after the onset of SRSs and suggests that deficits in mismatch novelty detection may substantially contribute to cognitive impairment in MTLE. As such, behavioural tasks based on these aspects of mismatch novelty may prove useful in the development of cognitive therapy strategies aiming to rescue cognitive deficits observed in epilepsy.
]]>Biomedicines doi: 10.3390/biomedicines12030630
Authors: Sara Gangi Laura Bergantini Paolo Cameli Irene Paggi Marco Spalletti Fabrizio Mezzasalma Elena Bargagli Miriana d’Alessandro
Introduction: Pulmonary fibrosis is an irreversible condition that may be caused by known (including viral triggers such as SARS-CoV-2) and unknown insults. The latter group includes idiopathic pulmonary fibrosis (IPF), which is a chronic, progressive fibrosing interstitial pneumonia of unknown cause. The longer the insult acts on lung tissue, the lower the probability of a complete resolution of the damage. An emerging clinical entity post-COVID-19 is pulmonary fibrosis (PCPF), which shares many pathological, clinical, and immunological features with IPF. The fibrotic response in both diseases—IPF and PCPF—is orchestrated in part by the immune system. An important role regarding the inhibitory or stimulatory effects on immune responses is exerted by the immune checkpoints (ICs). The aim of the present study was to analyse the similarities and differences between CD4+, CD8+, and NK cells in the peripheral blood of patients affected by fibrotic disease, IPF, and PCPF compared with sarcoidosis patients and healthy controls. The second aim was to evaluate the expression and co-expression of PD-1 and TIGIT on CD4, CD8, and NK cells from our patient cohort. Methods: One hundred and fifteen patients affected by IPF, PCPF, and sarcoidosis at the rare pulmonary disease centre of the University of Siena were enrolled. Forty-eight patients had an IPF diagnosis, 55 had PCPF, and 12 had sarcoidosis. Further, ten healthy controls were enrolled. PCPF patients were included between 6 and 9 months following hospital discharge for COVID-19. The peripheral blood samples were collected, and through flow cytometric analysis, we analysed the expression of CD4, CD8, NK cells, PD-1, and TIGIT. Results: The results show a greater depletion of CD4 and NK cells in IPF patients compared to other groups (p = 0.003), in contrast with CD8 cells (p < 001). Correlation analysis demonstrated an indirect correlation between CD4 and CD8 cells in IPF and sarcoidosis patients (p < 0.001 = −0.87 and p = 0.042; r = −0.6, respectively). Conversely, PCPF patients revealed a direct correlation between CD4 and CD8 cells (p < 0.001; r = 0.90) accentuating an immune response restoration. The expression of PD-1 and TIGIT was abundant on T and NK cell subsets of the two lung fibrotic groups, IPF and PCPF. Analogously, the co-expression of PD-1 and TIGIT on the surfaces of CD4 and CD8 were increased in such diseases. Conclusions: Our study shines a spotlight on the immune responses involved in the development of pulmonary fibrosis, idiopathic and secondary to SARS-CoV-2 infection. We observed a significant imbalance not only in CD4, CD8, and NK blood percentages in IPF and PCPF patients but also in their functional phenotypes evaluated through the expression of ICs.
]]>Biomedicines doi: 10.3390/biomedicines12030626
Authors: Ana Rita Monteiro Daniel José Barbosa Fernando Remião Renata Silva
The biological barriers existing in the human body separate the blood circulation from the interstitial fluid in tissues. The blood–brain barrier (BBB) isolates the central nervous system from the bloodstream, presenting a dual role: the protection of the human brain against potentially toxic/harmful substances coming from the blood, while providing nutrients to the brain and removing metabolites. In terms of architectural features, the presence of junctional proteins (that restrict the paracellular transport) and the existence of efflux transporters at the BBB are the two major in vivo characteristics that increase the difficulty in creating an ideal in vitro model for drug permeability studies and neurotoxicity assessments. The purpose of this work is to provide an up-to-date literature review on the current in vitro models used for BBB studies, focusing on the characteristics, advantages, and disadvantages of both primary cultures and immortalized cell lines. An accurate analysis of the more recent and emerging techniques implemented to optimize the in vitro models is also provided, based on the need of recreating as closely as possible the BBB microenvironment. In fact, the acceptance that the BBB phenotype is much more than endothelial cells in a monolayer has led to the shift from single-cell to multicellular models. Thus, in vitro co-culture models have narrowed the gap between recreating as faithfully as possible the human BBB phenotype. This is relevant for permeability and neurotoxicity assays, and for studies related to neurodegenerative diseases. Several studies with these purposes will be also presented and discussed.
]]>Biomedicines doi: 10.3390/biomedicines12030629
Authors: Miriam Almirall Marta Musté Mayte Serrat Rafael Touriño Esther Espartal Sara Marsal
Around 20–30% of Fibromyalgia patients modify their dietary habits after diagnosis, including avoiding certain food groups such as cereals. In this systematic review, we used the PRISMA guidelines to select the main studies that have evaluated the effectiveness of restrictive diets, including elimination and vegetarian diets, in patients with Fibromyalgia. Data on vegetarian/vegan diets are more consistent than data on elimination diets due to higher quality and better results of the published studies. Although the results are favorable in most of the studies, their heterogenicity and the scarce and low quality of the evidence (small number of patients included, often non-randomized and uncontrolled studies and multiple confounding factors and biases) does not allow for a positive recommendation about these restrictive diets in Fibromyalgia patients. Several factors other than food restriction could influence the symptomatic and functional improvements observed after restrictive diets, such as the placebo effect, weight loss that often occurs, coexistence with gastrointestinal diseases and positive effects of unrestricted foods. We must advance more and improve in our knowledge of the effectiveness of restrictive diets and variables related to them before recommending them systematically to all patients with Fibromyalgia. Randomized, placebo-controlled trials with large sample sizes, longer follow-up periods and standardized outcome measures that explore predictors of dietary response are needed to better understand the relationship between Fibromyalgia and nutrition.
]]>Biomedicines doi: 10.3390/biomedicines12030628
Authors: Kyung Soo Kim Taewon Kang Dong Wook Jekarl
The association between immune checkpoint inhibitors (ICIs) and immune gene networks in squamous lung cancer (LUSC) and lung adenocarcinoma (LUAD) was studied. Immune gene networks were constructed using RNA-seq data from the gene expression omnibus (GEO) database. Datasets with more than 10 samples of normal control and tumor tissues were selected; of these, GSE87340, GSE120622, and GSE111907 were suitable for analysis. Gene set enrichment for pathway analysis was performed. For immune gene network construction, 998 unique immune genes were selected from 21 pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG). Gene function annotation was performed based on the KEGG, Gene Ontology, and Reactome databases. Tumor tissues showed decreased coagulation, hematopoiesis, and innate immune pathways, whereas complement- and coagulation-related genes were prominent in the tumor immune gene network. The average numbers of neighbors, clustering coefficients, network diameters, path lengths, densities, and heterogeneities were highest for normal tissue, followed by LUAD and LUSC. Decreased coagulation genes, which were prominent in tumor immune networks, imply functional attenuation. LUAD was deviated from normal tissue, based on network parameters. Tumor tissues showed decreased immune function, and the deviation of LUSC from normal tissue might explain LUSC’s better therapeutic response to ICI treatment.
]]>Biomedicines doi: 10.3390/biomedicines12030627
Authors: Irina A. Mednova Ivan V. Pozhidaev Vladimir V. Tiguntsev Anna V. Bocharova Diana Z. Paderina Anastasiia S. Boiko Olga Y. Fedorenko Elena G. Kornetova Nikolay A. Bokhan Vadim A. Stepanov Svetlana A. Ivanova
Metabolic syndrome (MetS) is common among schizophrenia patients, and one of MetS’s causes may be an imbalance in nitric oxide regulation. In this study, we examined associations of three polymorphic variants of the nitric oxide synthase 1 adapter protein (NOS1AP) gene with MetS in schizophrenia. NOS1AP regulates neuronal nitric oxide synthase, which controls intracellular calcium levels and may influence insulin secretion. The aim of the investigation was to study polymorphic variants of the NOS1AP gene as possible markers of MetS in patients with schizophrenia. A total of 489 Caucasian patients with schizophrenia (ICD-10) from Siberia (Russia) were included in the study, and 131 (26.8%) patients had MetS (IDF classification, 2007). The participants were genotyped for three single-nucleotide polymorphisms in NOS1AP (rs12143842, rs10494366, and rs12029454). Logistic regression was used for association analysis. Single-nucleotide polymorphisms, sex, and age served as covariates; the dependent variable was the coded parameter of the presence/absence of MetS. Polymorphisms rs12143842 and rs10494366 showed a stable association even after Bonferroni’s correction for multiple comparisons (p = 0.005 and 0.002, respectively), indicating a statistically significant contribution of these polymorphic variants to the pathogenesis of MetS. Our results suggest that in patients with schizophrenia, NOS1AP may be involved in MetS pathophysiology.
]]>Biomedicines doi: 10.3390/biomedicines12030625
Authors: Khalid Saad Alharbi
Huntington’s disease (HD) is a neurodegenerative disease that causes progressive motor and cognitive dysfunction. There is no cure for HD, and current therapeutics can only manage the signs and symptoms as well as slowing disease progression. This investigation examines the possible therapeutic advantages of europinidin in 3-nitropropionic acid (3-NPA) injected HD in rats. Wistar rats were randomly assigned to five groups (n = 6): normal control, 3-NPA (10 mg/kg, i.p.), 3-NPA + europinidin-10 (10 mg/kg, p.o.), 3-NPA + europinidin-20 (20 mg/kg, p.o.), and europinidin alone (20 mg/kg, p.o.) for 15-day. Various behavioral and biochemical parameters including antioxidant levels, oxidative stress, pro-inflammatory markers, mitochondrial enzyme complex, and neurotransmitters were assessed. Europinidin restored biochemical, mitochondrial dysfunction, oxidative stress, neurotransmitter, and pro-inflammatory parameters disrupted by 3-NPA. Here we show that europinidin attenuates 3-NPA-induced neurodegeneration in rat models of HD. Europinidin modulates oxidative stress, enhances antioxidants, restores mitochondrial enzyme complex activity, reduces neuroinflammation, and modulates neurotransmitter levels. Our findings reveal the potential of europinidin as a novel therapeutic agent for the treatment of HD. This study also provides new insights into the molecular mechanisms of europinidin-mediated neuroprotection and may have a beneficial role in the management of neurological diseases.
]]>Biomedicines doi: 10.3390/biomedicines12030624
Authors: Shotaro Kamata Akihiro Honda Nonoka Kashiwagi Ayumi Shimamura Sayaka Yashiro Yuna Komori Aoi Hosoda Noriyuki Akahoshi Isao Ishii
Three peroxisome proliferator-activated receptor subtypes, PPARα, PPAR(ß/)δ, and PPARγ, exert ligand-dependent transcriptional control in concert with retinoid X receptors (RXRs) on various gene sets harboring PPAR response elements (PPREs) in their promoter regions. Ligand-bound PPAR/RXR complexes do not directly regulate transcription; instead, they recruit multiprotein coactivator complexes to specific genomic regulatory loci to cooperatively activate gene transcription. Several coactivators are expressed in a single cell; however, a ligand-bound PPAR can be associated with only one coactivator through a consensus LXXLL motif. Therefore, altered gene transcription induced by PPAR subtypes/agonists may be attributed to the recruitment of various coactivator species. Using a time-resolved fluorescence resonance energy transfer assay, we analyzed the recruitment of four coactivator peptides (PGC1α, CBP, SRC1, and TRAP220) to human PPARα/δ/γ-ligand-binding domains (LBDs) using eight PPAR dual/pan agonists (bezafibrate, fenofibric acid, pemafibrate, pioglitazone, elafibranor, lanifibranor, saroglitazar, and seladelpar) that are/were anticipated to treat nonalcoholic fatty liver disease. These agonists all recruited four coactivators to PPARα/γ-LBD with varying potencies and efficacy. Only five agonists (bezafibrate, pemafibrate, elafibranor, lanifibranor, and seladelpar) recruited all four coactivators to PPARδ-LBD, and their concentration-dependent responses differed from those of PPARα/γ-LBD. These results indicate that altered gene expression through consensus PPREs by different PPAR subtypes/agonists may be caused, in part, by different coactivators, which may be responsible for the unique pharmacological properties of these PPAR agonists.
]]>Biomedicines doi: 10.3390/biomedicines12030623
Authors: Kei Shimmyo Shigeru Obayashi
It is well known that cortical damage may affect cognitive functions, whereas subcortical damage, especially brainstem stroke, would be far less likely to cause cognitive decline, resulting in this condition being overlooked. Few studies have focused on cognitive dysfunction after a pontine stroke. Here, we begin with describing our nine new case reports of in-depth neuropsychological findings from patients with pontine stroke. The dominant domain of cognitive dysfunction was commonly characterized by executive dysfunction, almost in line with previous studies. The severity was relatively mild. We give an overview of the available literature on cognitive decline following a pontine stroke. This is followed by discussions regarding the prognosis of the cognitive disabilities. Based on previous neuroimaging findings, we would like to get to the core of the neuropathology underlying the cognitive declines in the context of “diaschisis”, a phenomenon of a broad range of brain dysfunctions remote from the local lesions. Specifically, our unique paper, with two modalities of neuroimaging techniques, may help us better understand the pathology. SPECT scans yield evidence of frontal and thalamic hyper-perfusion and cerebellar hypo-perfusion in patients with pontine stroke. Functional near-infrared spectroscopy, when focusing on the supplementary motor area (SMA) as one of the hyper-perfusion areas, exhibits that SMA responses may be subject to the severity of cognitive decline due to a pontine stroke and would also be related to the recovery. Finally, we posit that cognitive decline due to pontine stroke could be explained by the failure of hierarchical cognitive processing in the fronto–ponto–cerebellar–thalamic loop.
]]>Biomedicines doi: 10.3390/biomedicines12030622
Authors: Chen-Mao Liao Yi-Wei Kao Yi-Ping Chang Chih-Ming Lin
Chronic kidney disease (CKD) poses significant challenges to public health and healthcare systems, demanding a comprehensive understanding of its progressive nature. Prior methods have often fallen short in capturing the dynamic and individual variability of renal function. This study aims to address this gap by introducing a novel approach for the individualized assessment of CKD progression. A cohort of 1042 patients, comprising 700 with stage 3a and 342 with stage 3b to stage 5 CKD, treated at a veteran general hospital in Taiwan from 2006 to 2019, was included in the study. A comprehensive dataset spanning 12 years, consisting of clinical measurements, was collected and analyzed using joint models to predict the progression to hemodialysis treatment. The study reveals that the estimated glomerular filtration rate (eGFR) can be considered an endogenous factor influenced by innate biochemical markers. Serum creatinine, blood pressure, and urinary protein excretion emerged as valuable factors for predicting CKD progression. The joint model, combining longitudinal and survival analyses, demonstrated predictive versatility across various CKD severities. This innovative approach enhances conventional models by concurrently incorporating both longitudinal and survival analyses and provides a nuanced understanding of the variables influencing renal function in CKD patients. This personalized model enables a more precise assessment of renal failure risk, tailored to each patient’s unique clinical profile. The findings contribute to improving the management of CKD patients and provide a foundation for personalized healthcare interventions in the context of renal diseases.
]]>Biomedicines doi: 10.3390/biomedicines12030621
Authors: Hallie H. Dolin Robert W. Maitta
Thrombotic thrombocytopenic purpura (TTP) is an uncommon, but potentially disabling or even deadly, thrombotic microangiopathy with a well-studied mechanism of ADAMTS13 deficiency or dysfunction. While established treatments are largely effective, the standard ADAMTS13 testing required to definitively diagnose TTP may cause delays in diagnosis and treatment, highlighting the need for rapid and effective diagnostic methods. Additionally, the heterogeneous presentation and varied inciting events of TTP suggest more variation in its mechanism than previously thought, implying three potential pathways rather than the accepted two. The recent discovery of ADAMTS13 conformation as a potential contributor to TTP in addition to the proposal of using the absolute immature platelet count (A-IPC) as a biomarker, present novel areas for monitoring and treatment. A-IPC in particular may serve as a more rapid and accurate diagnostic test to distinguish TTP from non-TTP TMAs and to monitor treatment response and relapse. These considerations highlight the need to further study TTP in order to improve best practices and patient care.
]]>Biomedicines doi: 10.3390/biomedicines12030620
Authors: Adrian Martyniak Dorota Drożdż Przemysław J. Tomasik
Primary hypertension (PH) is the leading form of arterial hypertension (AH) in adolescents. Hypertension is most common in obese patients, where 20 to 40% of the population has elevated blood pressure. One of the most effective mechanisms for regulating blood pressure is the renin–angiotensin–aldosterone system (RAAS). The new approach to the RAAS talks about two opposing pathways between which a state of equilibrium develops. One of them is a classical pathway, which is responsible for increasing blood pressure and is represented mainly by the angiotensin II (Ang II) peptide and, to a lesser extent, by angiotensin IV (Ang IV). The alternative pathway is responsible for the decrease in blood pressure and is mainly represented by angiotensin 1–7 (Ang 1–7) and angiotensin 1–9 (Ang 1–9). Our research study aimed to assess changes in angiotensin II, angiotensin IV, angiotensin 1–7, and angiotensin 1–9 concentrations in the plasma of adolescents with hypertension, with hypertension and obesity, and obesity patients. The Ang IV concentration was lower in hypertension + obesity versus control and obesity versus control, respectively p = 0.01 and p = 0.028. The Ang 1–9 concentration was lower in the obesity group compared to the control group (p = 0.036). There were no differences in Ang II and Ang 1–7 peptide concentrations in the hypertension, hypertension and obesity, obesity, and control groups. However, differences were observed in the secondary peptides, Ang IV and Ang 1–9. In both cases, the differences were related to obesity.
]]>Biomedicines doi: 10.3390/biomedicines12030619
Authors: Marc Irqsusi Lan Anh Dong Fiona R. Rodepeter Rabia Ramzan Ildar Talipov Tamer Ghazy Madeline Günther Sebastian Vogt Ardawan J. Rastan
The pathogenesis of aortic aneurysm and dissection continues to be under discussion. Extracellular matrix (ECM) remodeling processes in the aortic wall are hypothesized to be involved in the development of the disorders. Therefore, in a histological study, we investigated the expression of metalloproteases 1 and 9 (MMP1 and MMP9) and their inhibitors (TIMP 1 and TIMP 2) in cardiac surgery patients. In parallel, we studied the aortic roots by echocardiography. Clinical reports of 111 patients (30 women and 81 men) who suffered from aortic aneurysms and aortic dissection were evaluated and studied by transesophageal echocardiography. Seven patients who had coronary heart disease served as “healthy controls”. All patients underwent the necessary surgical procedure according to the diagnosed aortic disease in the period from 2007 to 2015. A tissue sample of the aortic biopsies was collected from each patient during surgery. Immunohistochemical staining was performed for MMP1 and MMP9 and TIMP1 and TIMP2 as well. Vascularization was monitored by a CD 31 antibody. In direct comparison, the expressions are not homogeneous. We found the smallest changes in the intima area at all. TIMP 1 and TIMP 2 distribution increases from the lumen of the vessel outward in the wall layers of the aorta. In the case of arteriosclerotic changes, intima had a capillarization, but not in the media. An opposite pattern was found in the dissected aortas. There are differences in the vascularization between the aneurysm and dissection and the different layers, respectively. A different remodeling process of the ECM in comparison to the vascular layers must be hypothesized. Reading the patterns of staining and with regard to the known inhibitory effect of MMP9 on ECM remodeling, but especially TIMP 2 on neoangiogenesis, disturbed nutrition, and dysfunctional vasa vasorum remodeling must be assumed as causes of dissection.
]]>Biomedicines doi: 10.3390/biomedicines12030618
Authors: Tamara Jahmani Michael R. Miller Orlando da Silva Soume Bhattacharya
Minimally invasive surfactant therapy (MIST) has emerged as a preferred method of surfactant delivery. Pioneers of this technique have described the use of direct laryngoscopy (DL) for MIST. With the increasing application of video laryngoscopy (VL) for neonatal airway management, it is speculated that MIST techniques can be adapted for use with VL. Objective: To compare procedural success, operator ease of use, and complication of MIST using VL vs. MIST using DL. Methods: This was a retrospective, observational cohort study conducted at a tertiary-level neonatal intensive care unit after obtaining ethical approval. We included neonates who received MIST between 1 October 2020 and 31 October 2022. Baseline demographic characteristics, along with procedural data, were collected. Primary outcome measures included the overall procedural success rate, the need for multiple attempts, and the total number of attempts. Secondary outcome measures included the occurrence of adverse events, the need for a second dose of surfactant, and the need for intubation within 7 days of the procedure. Means and SDs, independent t-tests, frequencies, and chi-square were used as appropriate. p-values < 0.05 were considered statistically significant. Results: Of the 79 neonates included, 37 neonates received MIST via VL, while 42 received MIST via DL. The median gestational age was lower in the VL group at 29.0 weeks vs. 30.5 weeks (p = 0.011) in the DL group. The median birthweight in the VL group was 1260 g, IQR (1080, 1690), which was significantly lower than the DL group, which was 1575 g, IQR (1220, 2251), p = 0.028. Purpose-built catheter use was higher in the DL group. The overall procedural success was similar between groups. The need for multiple attempts was lower with VL in comparison to DL [4 (11%) vs. 13 (31%); p = 0.034)] at the univariate level but not significant at multivariate analysis (p = 0.131). Procedural complications, the need for a second dose of surfactant, the need for mechanical ventilation post-MIST, and operator ease of use were similar. User comments emphasized the value of VL in providing real-time visual information to confirm catheter placement and guide operators/trainees. Conclusion: Overall, in our cohort, despite VL being a more recently adapted technology used more in smaller, sicker, and more premature neonates, procedural success, complications, and operator ease of use for MIST using VL and DL were comparable. Our findings show the successful application of VL for MIST and suggest procedural advantages that might facilitate universal adoption.
]]>Biomedicines doi: 10.3390/biomedicines12030617
Authors: Gilberto Vargas-Alarcón Óscar Pérez-Méndez Rosalinda Posadas-Sánchez Héctor González-Pacheco María Luna-Luna Galileo Escobedo José Manuel Fragoso
Cholesterol-7-alpha hydroxylase (CYP7A1) is a key enzyme in the synthesis of bile salts, and its activity can contribute to determining cholesterol levels and, consequently, the risk of developing coronary atherosclerotic disease. We evaluated whether seven (rs3808607 G/T, rs9297994 G/A, rs10504255 A/G, rs8192870 G/T, rs2081687 C/T, rs1457043 C/T, and rs10107182 C/T) polymorphisms located in the promoter and enhancer regions of the CYP7A1 gene, which have not been sufficiently explored, are candidates of risk markers of acute coronary syndrome (ACS) in the Mexican population. These polymorphisms were determined in a group of 1317 patients with ACS and 1046 control subjects. The results showed that, under different inheritance models, the alleles rs9297994 G, rs10504255 G, rs8192870 T, rs2081687 T, and rs10107182 C were significantly associated with an increased risk of ACS (pC < 0.05). In addition, the incidence of dyslipidemia among patients with ACS, notably high total cholesterol and LDL-cholesterol, and low HDL-cholesterol plasma levels, were more frequent in carriers of the same five risk alleles associated with ACS (p < 0.05). There was also an unexpected increased incidence of type 2 diabetes mellitus (T2DM) in patients with ACS who are homozygous for the rs2081687 T, rs9297944 G, rs10504255 G, and rs10107182 C alleles of the CYP7A1 gene, suggesting that such gene variants enhance the development of coronary complications in patients with diabetes (p < 0.05). In summary, our study demonstrated that five polymorphisms situated in the promoter and enhancer regions of the CYP7A1 gene are associated with the risk of ACS and higher incidences of dyslipidemia and T2DM in Mexican patients with ACS.
]]>Biomedicines doi: 10.3390/biomedicines12030616
Authors: Serena Martinelli Giulia Nannini Fabio Cianchi Francesco Coratti Amedeo Amedei
Autoimmune diseases are complex multifactorial disorders, and a mixture of genetic and environmental factors play a role in their onset. In recent years, the microbiota has gained attention as it helps to maintain host health and immune homeostasis and is a relevant player in the interaction between our body and the outside world. Alterations (dysbiosis) in its composition or function have been linked to different pathologies, including autoimmune diseases. Among the different microbiota functions, there is the activation/modulation of immune cells that can protect against infections. However, if dysbiosis occurs, it can compromise the host’s ability to protect against pathogens, contributing to the development and progression of autoimmune diseases. In some cases, infections can trigger autoimmune diseases by several mechanisms, including the alteration of gut permeability and the activation of innate immune cells to produce pro-inflammatory cytokines that recruit autoreactive T and B cells. In this complex scenario, we cannot neglect critical hormones’ roles in regulating immune responses. Different hormones, especially estrogens, have been shown to influence the development and progression of autoimmune diseases by modulating the activity and function of the immune system in different ways. In this review, we summarized the main mechanisms of connection between infections, microbiota, immunity, and hormones in autoimmune diseases’ onset and progression given the influence of some infections and hormone levels on their pathogenesis. In detail, we focused on rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus.
]]>Biomedicines doi: 10.3390/biomedicines12030615
Authors: Jared Akers Emily Geisler Suimin Qiu Petros Konofaos Hisham Marwan
Odontogenic sarcomas are exceedingly rare and account for less than 5% of all Maxillofacial Sarcomas. It usually affects the younger population. The posterior mandible is the most commonly affected site. Radiographically, it appears as a large destructive radiolucent lesion with ill-defined margins. Histopathological diagnosis is usually difficult. Surgery is the mainstay treatment. The role of chemotherapy and radiation therapy is not clear. Here, we present a case study of a 30-year-old female patient diagnosed with odontogenic sarcoma that impinged on her airway. The treatment and postoperative course will be discussed in detail.
]]>Biomedicines doi: 10.3390/biomedicines12030614
Authors: Yu Liu Yu Xiao Jimeng Gao Jiaxin Gao Ruicheng Li Zhongquan Qi Xiaocun Liu
The treatment of spinal cord injury (SCI) is often ineffective. Additionally, SCI-induced inflammation leads to secondary injury. Current anti-inflammatory hydrophilic drugs fail to reach the nerve injury site due to the blood–brain barrier. Here, we synthesized MSR405, a new lipophilic unsaturated fatty acid derivative of Radix Isatidis and investigated its therapeutic effect in SCI model rats. Furthermore, we systematically investigated its structure, toxicity, anti-inflammatory effect, and the underlying mechanism. MSR405 was injected into the abdominal cavity of the Sprague Dawley SCI model rats, and the effect on their behavioral scores and pathology was estimated to assess the status of neurological inflammation. Our data show that MSR405 treatment significantly improved the motor function of SCI rats, and markedly suppressed the associated neuroinflammation. Moreover, MSR405 could attenuate LPS-induced inflammatory response in BV2 cells (Mouse microglia cells) in vitro. Mechanistically, MSR405 inhibits proinflammatory cytokines, supporting the anti-inflammatory response. Additionally, MSR405 can significantly block the TLR4/NF-κB signaling pathway and nitric oxide production. In summary, MSR405 reduces inflammation in SCI rats through the TLR4/NF-κB signal cascade and can inhibit neuroinflammation after spinal cord injury.
]]>Biomedicines doi: 10.3390/biomedicines12030613
Authors: Masaru Tanaka László Vécsei
Neuroscience, neurology, and psychiatry are rapidly evolving fields that aim to understand the complex mechanisms underlying brain function and dysfunction, as well as to develop effective interventions for various neurological and psychiatric disorders [...]
]]>Biomedicines doi: 10.3390/biomedicines12030612
Authors: Jeffery J. Nielsen Stewart A. Low Christopher Chen Xinlan Li Ephraim Mbachu Lina Trigg Siyuan Sun Madeline Tremby Rahul Hadap Philip S. Low
Spinal fusions are performed to treat congenital skeletal malformations, spondylosis, degenerative disk diseases, and other pathologies of the vertebrae that can be resolved by reducing motion between neighboring vertebrae. Unfortunately, up to 100,000 fusion procedures fail per year in the United States, suggesting that efforts to develop new approaches to improve spinal fusions are justified. We have explored whether the use of an osteotropic oligopeptide to target an attached bone anabolic agent to the fusion site might be exploited to both accelerate the mineralization process and improve the overall success rate of spinal fusions. The data presented below demonstrate that subcutaneous administration of a modified abaloparatide conjugated to 20 mer of D-glutamic acid not only localizes at the spinal fusion site but also outperforms the standard of care (topically applied BMP2) in both speed of mineralization (p < 0.05) and overall fusion success rate (p < 0.05) in a posterior lateral spinal fusion model in male and female rats, with no accompanying ectopic mineralization. Because the bone-localizing conjugate can be administered ad libitum post-surgery, and since the procedure appears to improve on standard of care, we conclude that administration of a bone-homing anabolic agent for improvement of spinal fusion surgeries warrants further exploration.
]]>Biomedicines doi: 10.3390/biomedicines12030611
Authors: Jung Il Choi Hyunjo Lee Dong Jun Kim Eun Suk Park Kyung Yeon Lee Hui-Jun Yang
The antihistamine astemizole has shown disease-modifying effects in several preclinical disease models of Parkinson’s disease (PD). Astemizole also interacts with an anomalous aggregation of Alzheimer’s disease-related amyloid-β (Aβ) peptide and has inhibitory activity on the human prion protein PrPSc. We hypothesized that the proposed preclinical benefits of astemizole on PD can be associated with the attenuation of pathological α-synuclein (α-syn) aggregation. We tested the effects of astemizole on the fibrillation processes of amyloid peptides using thioflavin T aggregation monitoring, Congo red spectral analysis, cell viability study, and transmission electron microscopic imaging. We found that astemizole did not inhibit α-syn aggregation in vitro even at a high molar ratio but inhibited the assembly of Aβ aggregates. Our results suggest that the inhibitory effect of astemizole on amyloid formation is target-protein selective, and the proposed beneficial effects of this compound observed in translational PD models might not be due to its ameliorating effects on α-syn aggregation.
]]>Biomedicines doi: 10.3390/biomedicines12030610
Authors: Irene Carrión-Barberà Laura Triginer Laura Tío Carolina Pérez-García Anna Ribes Victoria Abad Ana Pros Jordi Monfort Tarek Carlos Salman-Monte
It has been postulated that advanced glycation end products (AGEs) and their soluble receptor (sRAGE) may play a relevant role as inducers in the chronic inflammatory pathway in various conditions, among them, in immune-mediated diseases such as systemic lupus erythematosus (SLE). However, previous studies show conflicting results about their association with SLE characteristics and their usefulness as disease biomarkers. We aimed to study the association of specific serum AGEs (pentosidine, Nξ-(carboxymethyl)lysine (CML), Nξ-(carboxyethyl)lysine (CEL)), sRAGE levels and AGEs (specific serum AGEs and skin AGEs) to sRAGE ratios with various disease parameters, in order to clarify their potential as new biomarkers in SLE and to study their relationship with cardiovascular disease (CVD). To this aim, serum pentosidine, CML, CEL and sRAGE were measured via ELISA, and skin AGEs levels were measured by skin autofluorescence. Correlations of pentosidine levels with demographic and clinical data, indexes of activity, accrual damage and patient-reported outcomes were analyzed through multiple linear regression models, while correlations of the rest of the AGEs, sRAGE and AGE to sRAGE ratios (non-normal) were analyzed using both an OLS regression model and a GML. All of the analyses were adjusted for confounders. A total of 119 SLE patients were recruited. Serum AGEs and sRAGEs were significantly associated with SLE activity indexes and/or demographic or disease characteristics: pentosidine with pulmonary manifestations; CML with anti-dsDNA antibodies, IL-6, disease duration and non-Caucasian ethnicities; CEL with anti-dsDNA antibodies, IL-6 and accumulated number of manifestations; and sRAGE with male gender, photosensitivity and being on specific immunosuppressants. These results suggest that the AGE–sRAGE axis may serve as a novel biomarker for managing and prognosticating this disease. Its correlation with certain antibodies, demographics and disease presentations may indicate a distinct clinical phenotype associated with varying levels of AGEs and/or sRAGE. The significance of specific AGE/sRAGE ratios, introduced in this study for the first time, warrants additional investigation in forthcoming research. Our study did not confirm the link between serum AGEs and CVD, which merits further exploration through studies designed for this specific purpose.
]]>Biomedicines doi: 10.3390/biomedicines12030609
Authors: Fiona Verisqa Jeong-Hui Park Nandin Mandakhbayar Jae-Ryung Cha Linh Nguyen Hae-Won Kim Jonathan C. Knowles
Introduction: Osteogenic and angiogenic properties of synthetic bone grafts play a crucial role in the restoration of bone defects. Angiogenesis is recognised for its support in bone regeneration, particularly in larger defects. The objective of this study is to evaluate the new bone formation and neovascularisation of a 3D-printed isosorbide-based novel CSMA-2 polymer in biomimetic gyroid structures. Methods: The gyroid scaffolds were fabricated by 3D printing CSMA-2 polymers with different hydroxyapatite (HA) filler concentrations using the digital light processing (DLP) method. A small animal subcutaneous model and a rat calvaria critical-size defect model were performed to analyse tissue compatibility, angiogenesis, and new bone formation. Results: The in vivo results showed good biocompatibility of the 3D-printed gyroid scaffolds with no visible prolonged inflammatory reaction. Blood vessels were found to infiltrate the pores from day 7 of the implantation. New bone formation was confirmed with positive MT staining and BMP-2 expression, particularly on scaffolds with 10% HA. Bone volume was significantly higher in the CSMA-2 10HA group compared to the sham control group. Discussion and Conclusions: The results of the subcutaneous model demonstrated a favourable tissue response, including angiogenesis and fibrous tissue, indicative of the early wound healing process. The results from the critical-size defect model showcased new bone formation, as confirmed by micro-CT imaging and immunohistochemistry. The combination of CSMA-2 as the 3D printing material and the gyroid as the 3D structure was found to support essential events in bone healing, specifically angiogenesis and osteogenesis.
]]>Biomedicines doi: 10.3390/biomedicines12030608
Authors: Ivan Kraljević Sara Sablić Maja Marinović Guić Danijela Budimir Mršić Ivana Štula Krešimir Dolić Benjamin Benzon Vana Košta Krešimir Čaljkušić Marino Marčić Daniela Šupe Domić Sanja Lovrić Kojundžić
Acute ischemic stroke (AIS) is one of the leading causes of morbidity worldwide, thus, early recognition is essential to accelerate treatment. The only definite way to diagnose AIS is radiological imaging, which is limited to hospitals. However, two serum neuromarkers, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1), have been proven as indicators of brain trauma and AIS. We aimed to investigate the potential utility of these markers in distinguishing between large vessel occlusion (LVO) and small vessel occlusion (SVO), considering differences in treatment. Sixty-nine AIS patients were included in our study and divided into LVO and SVO groups based on radiological imaging. Control group consisted of 22 participants without history of neurological disorders. Results showed differences in serum levels of both GFAP and UHC-L1 between all groups; control vs. SVO vs. LVO (GFAP: 30.19 pg/mL vs. 58.6 pg/mL vs. 321.3 pg/mL; UCH-L1: 117.7 pg/mL vs. 251.8 pg/mL vs. 573.1 pg/mL; p < 0.0001), with LVO having the highest values. Other prognostic factors of stroke severity were analyzed and did not correlate with serum biomarkers. In conclusion, a combination of GFAP and UCH-L1 could potentially be a valuable diagnostic tool for differentiating LVO and SVO in AIS patients.
]]>Biomedicines doi: 10.3390/biomedicines12030607
Authors: María Peris-Fernández Marta Roca-Marugán Julià L. Amengual Ángel Balaguer-Timor Iris Viejo-Boyano Amparo Soldevila-Orient Ramon Devesa-Such Pilar Sánchez-Pérez Julio Hernández-Jaras
Chronic kidney disease (CKD) affects approximately 12% of the global population, posing a significant health threat. Inflammation plays a crucial role in the uremic phenotype of non-dialysis-dependent (NDD) stage 5 CKD, contributing to elevated cardiovascular and overall mortality in affected individuals. This study aimed to explore novel metabolic pathways in this population using semi-targeted metabolomics, which allowed us to quantify numerous metabolites with known identities before data acquisition through an in-house polar compound library. In a prospective observational design with 50 patients, blood samples collected before the initial hemodialysis session underwent liquid chromatography and high-resolution mass spectrometer analysis. Univariate (Mann–Whitney test) and multivariate (logistic regression with LASSO regularization) methods identified metabolomic variables associated with inflammation. Notably, adenosine-5′-phosphosulfate (APS), dimethylglycine, pyruvate, lactate, and 2-ketobutyric acid exhibited significant differences in the presence of inflammation. Cholic acid, homogentisic acid, and 2-phenylpropionic acid displayed opposing patterns. Multivariate analysis indicated increased inflammation risk with certain metabolites (N-Butyrylglycine, dimethylglycine, 2-Oxoisopentanoic acid, and pyruvate), while others (homogentisic acid, 2-Phenylpropionic acid, and 2-Methylglutaric acid) suggested decreased probability. These findings unveil potential inflammation-associated biomarkers related to defective mitochondrial fatty acid beta oxidation and branched-chain amino acid breakdown in NDD stage 5 CKD, shedding light on cellular energy production and offering insights for further clinical validation.
]]>Biomedicines doi: 10.3390/biomedicines12030606
Authors: Amankeldi A. Salybekov Markus Wolfien Waldemar Hahn Sumi Hidaka Shuzo Kobayashi
The use of artificial intelligence (AI) in healthcare is transforming a number of medical fields, including nephrology. The integration of various AI techniques in nephrology facilitates the prediction of the early detection, diagnosis, prognosis, and treatment of kidney disease. Nevertheless, recent reports have demonstrated that the majority of published clinical AI studies lack uniform AI reporting standards, which poses significant challenges in interpreting, replicating, and translating the studies into routine clinical use. In response to these issues, worldwide initiatives have created guidelines for publishing AI-related studies that outline the minimal necessary information that researchers should include. By following standardized reporting frameworks, researchers and clinicians can ensure the reproducibility, reliability, and ethical use of AI models. This will ultimately lead to improved research outcomes, enhanced clinical decision-making, and better patient management. This review article highlights the importance of adhering to AI reporting guidelines in medical research, with a focus on nephrology and urology, and clinical practice for advancing the field and optimizing patient care.
]]>Biomedicines doi: 10.3390/biomedicines12030605
Authors: Łukasz Lewandowski Agnieszka Bronowicka-Szydełko Maciej Rabczyński Dorota Bednarska-Chabowska Joanna Adamiec-Mroczek Adrian Doroszko Małgorzata Trocha Krzysztof Kujawa Agnieszka Matera-Witkiewicz Edwin Kuźnik Paweł Lubieniecki Marcin Madziarski Janusz Sokołowski Ewa A. Jankowska Katarzyna Madziarska
Due to the molecular mechanisms of action of antidiabetic drugs, they are considered to be effective in the treatment of both COVID-19 and the post-COVID-19 syndromes. The aim of this study was to determine the effect of administering insulin and metformin on the mortality of patients with type 2 diabetes (T2DM) with symptomatic COVID-19 with the use of logistic regression models. The association between death and insulin and metformin was weak and could not be included in the multivariate model. However, the interaction of both drugs with other factors, including remdesivir and low-molecular-weight heparin (metformin), age and hsCRP (insulin), modulated the odds of death. These interactions hint at multifaceted (anti-/pro-) associations of both insulin and metformin with the odds of death, depending on the patient’s characteristics. In the multivariate model, RDW-SD, adjusted with low-molecular-weight heparin treatment, age, sex and K+, was associated with mortality among patients with COVID-19 and T2DM. With a 15% increase in RDW-SD, the risk of death increased by 87.7%. This preliminary study provides the foundations for developing further, more personalized models to assess the risk of death in T2DM patients, as well as for identifying patients at an increased risk of death due to COVID-19.
]]>Biomedicines doi: 10.3390/biomedicines12030604
Authors: Boyun Kim Jewon Jung
Obesity is recognized as a significant risk factor for ovarian cancer, with accumulating evidence highlighting its impact on disease progression and chemoresistance. This review synthesizes current research elucidating the link between obesity-induced lysosomal dysfunction and ovarian cancer chemoresistance. Epidemiological studies consistently demonstrate a positive correlation between body mass index (BMI) and ovarian cancer risk, attributed in part to the predilection of epithelial ovarian cancer cells for adipose tissue, particularly the omentum. Adipokines released from the omentum contribute to cancer-associated characteristics, including energy supply to cancer cells. Moreover, obesity-induced alterations in lysosomal function have been implicated in systemic inflammation and lipid metabolism dysregulation, further exacerbating cancer progression. Lysosomes play a crucial role in drug resistance, as evidenced by studies demonstrating their involvement in mediating resistance to chemotherapy in ovarian cancer cells. Recent findings suggest that pharmacological inhibition of lysosomal calcium channels sensitizes drug-resistant ovarian cancer cells to cisplatin treatment, highlighting the therapeutic potential of targeting lysosomal dysfunction in obesity-related chemoresistance. This review underscores the importance of understanding the multifaceted roles of lysosomes in obesity-related drug resistance and their implications for the development of targeted therapeutic interventions in ovarian cancer management.
]]>Biomedicines doi: 10.3390/biomedicines12030603
Authors: Ewud Agborbesong Julie Xia Zhou Hongbing Zhang Linda Xiaoyan Li Peter C. Harris James P. Calvet Xiaogang Li
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder worldwide and progresses to end-stage renal disease (ESRD). However, its precise mechanism is not fully understood. In recent years, epigenetic reprogramming has drawn increasing attention regarding its effect on cyst growth. However, considering the complexity of epigenetic mechanisms and the broad range of alterations of epigenetic components in ADPKD, identifying more specific epigenetic factors and understanding how they are mechanistically linked to promote cyst growth is relevant for the development of treatment for ADPKD. Here, we find that the histone methyltransferase SMYD3, which activates gene transcription via histone H3 lysine 4 trimethylation (H3K4me3), is upregulated in PKD1 mutant mouse and human ADPKD kidneys. Genetic knockout of SMYD3 in a PKD1 knockout mouse model delayed cyst growth and improved kidney function compared with PKD1 single knockout mouse kidneys. Immunostaining and Western blot assays indicated that SMYD3 regulated PKD1-associated signaling pathways associated with proliferation, apoptosis, and cell cycle effectors in PKD1 mutant renal epithelial cells and tissues. In addition, we found that SMYD3 localized to the centrosome and regulated mitosis and cytokinesis via methylation of α-tubulin at lysine 40. In addition, SMYD3 regulated primary cilia assembly in PKD1 mutant mouse kidneys. In summary, our results demonstrate that overexpression of SMYD3 contributes to cyst progression and suggests targeting SMYD3 as a potential therapeutic strategy for ADPKD.
]]>Biomedicines doi: 10.3390/biomedicines12030602
Authors: Irving Alejandro Carrillo-Dávila Asbiel Felipe Garibaldi-Ríos Luis E. Figuera Belinda Claudia Gómez-Meda Guillermo M. Zúñiga-González Ana María Puebla-Pérez Patricia Montserrat García-Verdín Paola Beatriz Castro-García Itzae Adonai Gutiérrez-Hurtado Blanca Miriam Torres-Mendoza Martha Patricia Gallegos-Arreola
The aim of this study was to associate FGFR4 rs1966265 and rs351855 variants with colorectal cancer (CRC) in a Mexican population and to perform in silico analysis. Genomic DNA from 412 healthy individuals and 475 CRC patients was analyzed. In silico analysis was performed using the PolyPhen-V2, GEPIA, GTEx, and Cytoscape platforms. The GA genotype dominant model (GAAA) of rs1966265 and the AA genotype dominant and recessive models of rs351855 were identified as CRC risk factors (p < 0.05). CRC patients aged ≥ 50 years at diagnosis who consumed alcohol had a higher incidence of the rs351855 GA genotype than the control group (p < 0.05). Associations were observed between the rs1966265 GA genotype and patients with rectal cancer and stage III–IV disease. The rs351855 AA genotype was a risk factor for partial chemotherapy response, and the GA + AA genotype for age ≥ 50 years at diagnosis and rectal cancer was associated with a partial response to chemotherapy (p < 0.05). The AA haplotype was associated with increased susceptibility to CRC. In silico analysis indicated that the rs351855 variant is likely pathogenic (score = 0.998). Genotypic expression analysis in blood samples showed statistically significant differences (p < 0.05). EFNA4, SLC3A2, and HNF1A share signaling pathways with FGFR4. Therefore, rs1966265 and rs351855 may be potential CRC risk factors.
]]>Biomedicines doi: 10.3390/biomedicines12030601
Authors: Józefa Dąbek Dariusz Korzeń Oskar Sierka Lech Paluszkiewicz Hendrik Milting Zbigniew Gąsior
The aim of the study was to assess the occurrence of classic risk factors in the study group of patients with heart failure and to link them with the transcriptional activity of the examined genes: metalloproteinase 9 (MMP-9) and the tissue inhibitor of metalloproteinases 1 (TIMP-1). A total of 150 (100%) patients qualified for the study, including 80 (53.33%) patients with heart failure in the course of coronary artery disease, 40 (26.67%) with coronary artery disease without heart failure, and 30 (20.00%) in whom the presence of atherosclerotic changes in the coronary arteries was excluded. The material for molecular tests was peripheral blood collected from patients within the first 24 h of hospitalisation. A quantitative analysis of transcriptional activity was performed using the RT-qPCR technique. The most common classic risk factors among the patients in the study group were arterial hypertension (117; 78.00%) and overweight/obesity (102; 68%). In the group of patients with coronary artery disease and heart failure burdened with overweight/obesity, a significantly higher transcriptional activity of the metalloproteinase 9 (MMP-9) gene was found in comparison to patients who were not burdened with this risk factor. The analysis also showed the statistically significant higher transcriptional activity of the metalloproteinase 9 (MMP-9) gene in a group of patients with coronary artery disease and heart failure who smoked. The examined patients with heart failure due to myocardial ischemia were burdened with numerous cardiovascular risk factors, the most common of which were arterial hypertension, obesity/overweight, and hypercholesterolemia. A significant increase in the transcriptional activity of the metalloproteinase 9 (MMP-9) gene in the presence of risk factors (male sex, overweight/obesity, smoking) indicates another pathomechanism of their action and participation in the development and progression of heart failure during myocardial ischemia. There is a need for systematic information and educational activities promoting a healthy lifestyle with the elimination of modifiable risk factors for cardiovascular diseases.
]]>Biomedicines doi: 10.3390/biomedicines12030600
Authors: Dominika Sabiniewicz-Ziajka Arkadiusz Szarmach Małgorzata Grzywińska Paweł Gać Maciej Piskunowicz
Background: Computed tomography (CT) contributes significantly to the collective dose from medical sources, raising concerns about potential health risks. However, existing radiation dose estimation tools, such as volume computed tomography dose index (CTDIvol), dose-length product (DLP), effective dose (ED), and size-specific dose estimate (SSDE), have limitations in accurately reflecting patient exposure. This study introduces a new parameter, size-specific dose-length product (DLPss), aiming to enhance the precision of radiation dose estimation in real-life scenarios. Methods: A retrospective analysis of 134 chest CT studies was conducted. Relationships between CTDIvol and anthropometric parameters were examined, and SSDE was calculated based on effective diameter. Additionally, the novel parameter, DLPss, was introduced, considering scan length and cross-sectional dimensions. Results: Analysis reveals variations in scan length, effective diameter, and CTDIvol between genders. Strong correlations were observed between CTDIvol and effective diameter, particularly in men. The average CTDIvol for the entire group was 7.83 ± 2.92 mGy, with statistically significant differences between women (7.38 ± 3.23 mGy) and men (8.30 ± 2.49 mGy). SSDE values showed significant gender differences, with men exhibiting higher values. The average SSDE values for women and men were 9.15 ± 2.5 mGy and 9.6 ± 2.09 mGy, respectively, with a statistically significant difference (p = 0.03). The newly introduced DLPss values ranged around 343.90 ± 81.66 mGy·cm for the entire group, with statistically significant differences between women (323.53 ± 78.69 mGy·cm) and men (364.89 ± 79.87 mGy·cm) (p < 0.05), providing a comprehensive assessment of total radiation dose. Conclusion: The study highlights the need for accurate radiation dose estimation, emphasizing the impact of CT examination parameters on dose variability. The proposed DLPss parameter offers a promising approach to enhancing precision in assessing radiation risk during CT scans. Further research is warranted to explore additional parameters for a comprehensive understanding of radiation exposure and to optimize imaging protocols for patient safety.
]]>Biomedicines doi: 10.3390/biomedicines12030596
Authors: Monika Skrzypiec-Spring Maciej Kaczorowski Alina Rak-Pasikowska Agnieszka Sapa-Wojciechowska Krzysztof Kujawa Agnieszka Żuryń Iwona Bil-Lula Agnieszka Hałoń Adam Szeląg
Many studies have proven the involvement of the RhoA/ROCK pathway in autoimmune and cardiovascular diseases and the beneficial effects of its downregulation. Here, we examined whether the effect of simvastatin on experimental autoimmune myocarditis (EAM) may be through targeting the Ras homolog family member A/Rho-associated coiled-coil containing kinases (RhoA/ROCK) pathway and whether previously shown downregulation of metalloproteinase 9 (MMP-9) could be associated with MLC phosphorylation. Two doses of simvastatin were administered to experimental rats with autoimmune myocarditis by gastric gavage for 3 weeks, at the stage of development of the inflammatory process. Immunohistochemical staining for RhoA and ROCK1 was evaluated semi-quantitatively with H-score. The RhoA staining showed no significant differences in expression between the groups, but the ROCK1 expression was significantly upregulated in the hearts of the EAM group and was not downregulated by simvastatin. The Western blotting analysis of the last downstream product of the RhoA/ROCK axis, phosphorylated myosin light chain (phospho-MYL9), revealed that protein content increased in EAM hearts and it was prevented by the highest dose of simvastatin. Our findings suggest that the RhoA/ROCK pathway is upregulated in EAM, and simvastatin in EAM settings inhibits the RhoA/ROCK pathway at the stage of phosphorylation of myosin light chains and provides a new insight into the molecular pathology of autoimmune myocarditis.
]]>Biomedicines doi: 10.3390/biomedicines12030598
Authors: Michael Phan Maria A. Gomes Victoria Stinnett Laura Morsberger Nicole L. Hoppman Kathryn E. Pearce Kirstin Smith Brian Phan Liqun Jiang Ying S. Zou
Complex structural chromosome abnormalities such as chromoanagenesis have been reported in acute myeloid leukemia (AML). They are usually not well characterized by conventional genetic methods, and the characterization of chromoanagenesis structural abnormalities from short-read sequencing still presents challenges. Here, we characterized complex structural abnormalities involving chromosomes 2, 3, and 7 in an AML patient using an integrated approach including CRISPR/Cas9-mediated nanopore sequencing, mate pair sequencing (MPseq), and SNP microarray analysis along with cytogenetic methods. SNP microarray analysis revealed chromoanagenesis involving chromosomes 3 and 7, and a pseudotricentric chromosome 7 was revealed by cytogenetic methods. MPseq revealed 138 structural variants (SVs) as putative junctions of complex rearrangements involving chromosomes 2, 3, and 7, which led to 16 novel gene fusions and 33 truncated genes. Thirty CRISPR RNA (crRNA) sequences were designed to map 29 SVs, of which 27 (93.1%) were on-target based on CRISPR/Cas9 crRNA nanopore sequencing. In addition to simple SVs, complex SVs involving over two breakpoints were also revealed. Twenty-one SVs (77.8% of the on-target SVs) were also revealed by MPseq with shared SV breakpoints. Approximately three-quarters of breakpoints were located within genes, especially intronic regions, and one-quarter of breakpoints were intergenic. Alu and LINE repeat elements were frequent among breakpoints. Amplification of the chromosome 7 centromere was also detected by nanopore sequencing. Given the high amplification of the chromosome 7 centromere, extra chromosome 7 centromere sequences (tricentric), and more gains than losses of genomic material, chromoanasynthesis and chromothripsis may be responsible for forming this highly complex structural abnormality. We showed this combination approach’s value in characterizing complex structural abnormalities for clinical and research applications. Characterization of these complex structural chromosome abnormalities not only will help understand the molecular mechanisms responsible for the process of chromoanagenesis, but also may identify specific molecular targets and their impact on therapy and overall survival.
]]>Biomedicines doi: 10.3390/biomedicines12030599
Authors: Jennifer Moritz Antonia Schwab Andreas Reinisch Armin Zebisch Heinz Sill Albert Wölfler
Acute myeloid leukemia (AML) is an aggressive malignant disease with a high relapse rate due to the persistence of chemoresistant cells. To some extent, these residual cells can be traced by sensitive flow cytometry and molecular methods resulting in the establishment of measurable residual disease (MRD). The detection of MRD after therapy represents a significant prognostic factor for predicting patients’ individual risk of relapse. However, due to the heterogeneity of the disease, a single sensitive method for MRD detection applicable to all AML patients is lacking. This review will highlight the advantages and limitations of the currently available detection methods—PCR, multiparameter flow cytometry, and next generation sequencing—and will discuss emerging clinical implications of MRD test results in tailoring treatment of AML patients.
]]>Biomedicines doi: 10.3390/biomedicines12030597
Authors: Estela Sangüesa Emilio Fernández-Egea Julia Concha Cristina B. García María Pilar Ribate
Managing schizophrenia with clozapine poses a significant challenge due to prevalent therapeutic failures. The increasing interest in personalized medicine underscores the importance of integrating pharmacogenetic information for effective pharmacotherapeutic monitoring in patients. The objective of this study was to explore the correlation between DRD2, HTR2A, SLC6A4, CYP1A2, and ABCB1 polymorphisms and clozapine response in 100 patients with Treatment-Resistant Schizophrenia. Different scales such as the Positive and Negative Syndrome Scale (PANSS), the Warwick-Edinburgh Mental Wellbeing Scale (SWEMWBS), the Global Assessment of Functioning Scale (GAF), the Brief Negative Symptom Scale (BNSS), and pharmacokinetic parameters were used to analyse the efficacy of the treatment. Patients who exclusively responded to clozapine compared to the patients with augmentation strategies exhibited distinctive features, such as lower doses, plasma levels, and presented less-pronounced symptomatology. Genetic associations were explored, highlighting SLC6A4, HTR2A, and the *1F/*1F polymorphism for the CYP1A2 gene.
]]>Biomedicines doi: 10.3390/biomedicines12030595
Authors: Monika Kulaszyńska Sebastian Kwiatkowski Karolina Skonieczna-Żydecka
Iron is the micronutrient with the best-studied biological functions. It is widely distributed in nature, and its involvement in the main metabolic pathways determines the great importance of this metal for all organisms. Iron is required for cellular respiration and various biochemical processes that ensure the proper functioning of cells and organs in the human body, including the brain. Iron also plays an important role in the production of free radicals, which can be beneficial or harmful to cells under various conditions. Reviews of iron metabolism and its regulation can be found in the literature, and further advances in understanding the molecular basis of iron metabolism are being made every year. The aim of this review is to systematise the available data on the role of iron in the function of the nervous system, especially in the brain. The review summarises recent views on iron metabolism and its regulatory mechanisms in humans, including the essential action of hepcidin. Special attention is given to the mechanisms of iron absorption in the small intestine and the purpose of this small but critically important pool of iron in the brain.
]]>Biomedicines doi: 10.3390/biomedicines12030594
Authors: Sibylle Béchet Kumlesh K. Dev
Krabbe’s disease (KD) is caused by mutations in the lysosomal enzyme galactocerebrosidase and is associated with psychosine toxicity. The sphingosine 1-phosphate receptor (S1PR) agonist fingolimod (FTY720) attenuates psychosine-induced cell death of human astrocytes, demyelination in cerebellar slices, as well as demyelination in the central nervous system of twitcher mice. Psychosine also accumulates in the peripheral nervous system in twitcher mice; however, effects of fingolimod on this peripheral myelin have not been examined. The aim of this study was to investigate the effects of fingolimod administration on peripheral and central markers of myelination. Here, we report that fingolimod administration (1 mg/kg/day) from postnatal day 5 (PND) onwards did not alter peripheral demyelination in the sciatic nerve of twitcher mice, despite significantly reducing myelin debris, glial reactivity, and neuronal damage in the cerebellum. We also find fingolimod administration improves twitching and mobility scores in twitcher mice. Importantly, we find that fingolimod significantly increases the lifespan of twitcher mice by approximately 5 days. These findings suggest differential effects of fingolimod on peripheral and central neuropathy in twitcher mice, which may explain its modest efficacy on behavior and lifespan.
]]>Biomedicines doi: 10.3390/biomedicines12030593
Authors: Gyongyver Szentmartoni Dorottya Mühl Renata Csanda Attila Marcell Szasz Zoltan Herold Magdolna Dank
Ten percent of patients with breast cancer, and probably somewhat more in patients with ovarian cancer, have inherited germline DNA mutations in the breast and ovarian cancer genes BRCA1 and BRCA2. In the remaining cases, the disease is caused by acquired somatic genetic and epigenetic alterations. Targeted therapeutic agents, such as poly ADP-ribose polymerases (PARP) inhibitors (PARPi), have emerged in treating cancers associated with germline BRCA mutations since 2014. The first PARPi was FDA-approved initially for ovarian cancer patients with germline BRCA mutations. Deleterious variants in the BRCA1/BRCA2 genes and homologous recombination deficiency status have been strong predictors of response to PARPi in a few solid tumors since then. However, the relevance of somatic BRCA mutations is less clear. Somatic BRCA-mutated tumors might also respond to this new class of therapeutics. Although the related literature is often controversial, recently published case reports and/or randomized studies demonstrated the effectiveness of PARPi in treating patients with somatic BRCA mutations. The aim of this review is to summarize the predictive role of somatic BRCA mutations and to provide further assistance for clinicians with the identification of patients who could potentially benefit from PARPi.
]]>Biomedicines doi: 10.3390/biomedicines12030592
Authors: Lena Guerrero-Navarro Ines Martic Christian Ploner Pidder Jansen-Dürr Maria Cavinato
Cellular senescence, a state of irreversible growth arrest, is implicated in various age-related pathologies, including skin aging. In this study, we investigated the role of CLCA2, a calcium-activated chloride channel accessory protein, in cellular senescence and its implications for skin aging. Utilizing UVB and Nutlin3a-induced senescence models, we observed the upregulation of CLCA2 at both transcriptomic and proteomic levels, suggesting its involvement in senescence pathways. Further analysis revealed that the depletion of CLCA2 led to accelerated senescence onset, characterized by classic senescence markers and a unique secretome profile. In 3D skin equivalent models, SEs constructed with CLCA2 knockdown fibroblasts exhibited features reminiscent of aged skin, underscoring the importance of CLCA2 in maintaining skin homeostasis. Our findings highlight CLCA2 as a novel regulator of cellular senescence and its potential implications for skin aging mechanisms.
]]>Biomedicines doi: 10.3390/biomedicines12030591
Authors: Rita Saúde-Conde Ayça Arçay Öztürk Kosta Stosic Oier Azurmendi Senar Julie Navez Christelle Bouchart Tatjana Arsenijevic Patrick Flamen Jean-Luc Van Laethem
Pancreatic ductal adenocarcinoma (PDAC) represents a formidable challenge due to its aggressive nature and poor prognosis. The tumor microenvironment (TME) in PDAC, characterized by intense stromal desmoplastic reactions and a dominant presence of cancer-associated fibroblasts (CAFs), significantly contributes to therapeutic resistance. However, within the heterogeneous CAF population, fibroblast activation protein (FAP) emerges as a promising target for Gallium-68 FAP inhibitor positron emission tomography (Ga68FAPI-PET) imaging. Notably, 68Ga-FAPI-PET demonstrates promising diagnostic sensitivity and specificity, especially in conjunction with low tracer uptake in non-tumoral tissues. Moreover, it provides valuable insights into tumor–stroma interactions, a critical aspect of PDAC tumorigenesis not adequately visualized through conventional methods. The clinical implications of this innovative imaging modality extend to its potential to reshape treatment strategies by offering a deeper understanding of the dynamic TME. However, while the potential of 68Ga-FAPI-PET is evident, ongoing correlative studies are essential to elucidate the full spectrum of CAF heterogeneity and to validate its impact on PDAC management. This article provides a comprehensive review of CAF heterogeneity in PDAC and explores the potential impact of 68Ga-FAPI-PET on disease management.
]]>Biomedicines doi: 10.3390/biomedicines12030589
Authors: Yuchen Chen Xue-Jun Song
Diabetic neuropathic pain (DNP) is one of the common and severe late-stage complications of diabetes mellitus, which could greatly influence the patients’ quality of life. Patients with DNP often experience spontaneous pain and evoked pain such as mechanical allodynia and thermal hyperalgesia, meaning that their physical and psychological health are severely impaired. Unfortunately, the mechanisms of DNP remain highly elusive, so substantial breakthrough in effective DNP targeted treatments is still clinically challenging. This article will hence summarise the main mechanisms currently known to underlie DNP pathogenesis, along with describing some of the current and potential treatment methods against diabetic neuropathic pain.
]]>Biomedicines doi: 10.3390/biomedicines12030590
Authors: Christophe Desterke Fanny Jaulin Emmanuel Dornier
Colorectal cancer (CRC) is the second cause of cancer-related death; the CpG-island methylation pathway (CIMP) is associated with KRAS/BRAF mutations, two oncogenes rewiring cell metabolism, worse prognosis, and resistance to classical chemotherapies. Despite this, the question of a possible metabolic rewiring in CIMPs has never been investigated. Here, we analyse whether metabolic dysregulations are associated with tumour methylation by evaluating the transcriptome of CRC tumours. CIMP-high patients were found to present a hypermetabolism, activating mainly carbohydrates, folates, sphingolipids, and arachidonic acid metabolic pathways. A third of these genes had epigenetic targets of Myc in their proximal promoter, activating carboxylic acid, tetrahydrofolate interconversion, nucleobase, and oxoacid metabolisms. In the Myc signature, the expression of GAPDH, TYMS, DHFR, and TK1 was enough to predict methylation levels, microsatellite instability (MSI), and mutations in the mismatch repair (MMR) machinery, which are strong indicators of responsiveness to immunotherapies. Finally, we discovered that CIMP tumours harboured an increase in genes involved in the one-carbon metabolism, a pathway critical to providing nucleotides for cancer growth and methyl donors for DNA methylation, which is associated with worse prognosis and tumour hypermethylation. Transcriptomics could hence become a tool to help clinicians stratify their patients better.
]]>Biomedicines doi: 10.3390/biomedicines12030586
Authors: Maria Siemionow Katarzyna Budzynska Kristina Zalants Paulina Langa Sonia Brodowska Krzysztof Siemionow Ahlke Heydemann
Duchenne Muscular Dystrophy (DMD) is a lethal disease caused by mutation in the dystrophin gene. Currently there is no cure for DMD. We introduced a novel human Dystrophin Expressing Chimeric (DEC) cell therapy of myoblast origin and confirmed the safety and efficacy of DEC in the mdx mouse models of DMD. In this study, we assessed histological and morphological changes in the cardiac, diaphragm, and gastrocnemius muscles of the mdx/scid mice after the transplantation of human DEC therapy via the systemic-intraosseous route. The efficacy of different DEC doses was evaluated at 90 days (0.5 × 106 and 1 × 106 DEC cells) and 180 days (1 × 106 and 5 × 106 DEC cells) after administration. The evaluation of Hematoxylin & Eosin (H&E)-stained sectional slices of cardiac, diaphragm, and gastrocnemius muscles included assessment of muscle fiber size by minimal Feret’s diameter method using ImageJ software. The overall improvement in muscle morphology was observed in DMD-affected target muscles in both studies, as evidenced by a shift in fiber size distribution toward the wild type (WT) phenotype and by an increase in the mean Feret’s diameter compared to the vehicle-injected controls. These findings confirm the long-term efficacy of human DEC therapy in the improvement of overall morphological pathology in the muscles affected by DMD and introduce DEC as a novel therapeutic approach for DMD patients.
]]>Biomedicines doi: 10.3390/biomedicines12030588
Authors: Dwight D. Harris Sharif A. Sabe Mark Broadwin Christopher Stone Cynthia Xu Jiayu Hu Meghamsh Kanuparthy M. Ruhul Abid Frank W. Sellke
Background: Sodium–glucose cotransporter-2 (SGLT2) inhibitors are known to be cardioprotective independent of glucose control, but the mechanisms of these benefits are unclear. We previously demonstrated improved cardiac function and decreased fibrosis in a swine model of chronic myocardial ischemia. The goal of this study is to use high-sensitivity proteomic analyses to characterize specific molecular pathways affected by SGLT-2 inhibitor canagliflozin (CAN) therapy in a swine model of chronic myocardial ischemia. Methods: Chronic myocardial ischemia was induced in sixteen Yorkshire swine via the placement of an ameroid constrictor to the left circumflex coronary artery. After two weeks of recovery, swine received either 300 mg of CAN daily (n = 8) or a control (n = 8). After five weeks of therapy, the group of swine were euthanized, and left ventricular tissue was harvested and sent for proteomic analysis. Results: Total proteomic analysis identified a total of 3256 proteins between the CAN and control groups. Three hundred and five proteins were statistically different. This included 55 proteins that were downregulated (p < 0.05, fold change <0.5) and 250 that were upregulated (p < 0.05, fold change >2) with CAN treatment. Pathway analysis demonstrated the upregulation of several proteins involved in metabolism and redox activity in the CAN-treated group. The CAN group also exhibited a downregulation of proteins involved in motor activity and cytoskeletal structure. Conclusions: In our swine model of chronic myocardial ischemia, CAN therapy alters several proteins involved in critical molecular pathways, including redox regulation and metabolism. These findings provide additional mechanistic insights into the cardioprotective effects of canagliflozin.
]]>Biomedicines doi: 10.3390/biomedicines12030587
Authors: Marija V. Medovic Vesna M. Milicic Ana B. Ravic Nikolic Gordana J. Ristic Rasa H. Medovic Marina R. Nikolic Aleksandra Z. Stojanovic Sergey B. Bolevich Natalia G. Bondarchuk Alexander A. Gorbunov Slobodanka L. Mitrovic Vladimir Lj. Jakovljevic Ivan M. Srejovic
Given that oxidative stress represents an important etiological factor in the pathogenesis of psoriasis, the aim of this study was to assess the effects of different therapeutic approaches, methotrexate, secukinumab, and ustekinumab on systemic oxidative stress biomarkers in psoriatic patients. This study involved 78 psoriatic patients, divided into the group treated with methotrexate (23 patients), secukinumab (28 patients), and ustekinumab (27 patients), and 15 healthy controls. Oxidative stress biomarkers (index of lipid peroxidation measured as TBARS, nitrites (NO2−), superoxide anion radical (O2−), and hydrogen peroxide (H2O2)) and antioxidative defense system (superoxide dismutase (SOD) activity, catalase (CAT) activity, and reduced glutathione (GSH)) were determined spectrophotometrically from the blood before the initiation of therapy in 16th, 28th, and 52nd week. O2− and SOD showed the most prominent changes comparing the psoriatic patients and healthy controls. CAT activity was significantly lower in psoriatic patients, and methotrexate induced a further decline in CAT activity. Ustekinumab induced a significant increase in GSH level after 52 weeks of treatment, while methotrexate reduced GSH. All applied therapeutic options induced a reduction in PASI, BSA, DLQI, and EARP. Biological drugs exert more pronounced antioxidant effects compared to methotrexate, which is most clearly observed in the values of O2− and SOD.
]]>Biomedicines doi: 10.3390/biomedicines12030585
Authors: Preeti Kumari Chaudhary Sachin Upadhayaya Sanggu Kim Soochong Kim
Cardiovascular thromboembolic diseases and cancer continue to be a leading cause of death and disability worldwide. Therefore, it is crucial to advance their diagnoses and treatment in the context of individualized medicine. However, the disease specificity of the currently available markers is limited. Based on analyses of a subset of peptides and matching proteins in disease vs. healthy platelets, scientists have recently shown that focused platelet proteomics enables the quantification of disease-specific biomarkers in humans. In this review, we explored the potential of accurate platelet proteomic research, which is required to identify novel diagnostic and pharmaceutical targets by comprehending the proteome variety of healthy individuals and patients for personalized and precision medicine.
]]>Biomedicines doi: 10.3390/biomedicines12030584
Authors: Pierre Layrolle Christophe Orssaud Maryse Leleu Pierre Payoux Stéphane Chavanas
Optic neuropathies are characterized by the degeneration of the optic nerves and represent a considerable individual and societal burden. Notably, Leber’s hereditary optic neuropathy (LHON) is a devastating vision disease caused by mitochondrial gene mutations that hinder oxidative phosphorylation and increase oxidative stress, leading to the loss of retinal ganglion neurons and axons. Loss of vision is rapid and severe, predominantly in young adults. Penetrance is incomplete, and the time of onset is unpredictable. Recent findings revealed that the incidence of genetic LHON susceptibility is around 1 in 1000, much higher than believed till now. Environmental factors are critical in LHON triggering or severity. Families at risk have a very strong demand for how to prevent the onset or limit the severity of the disease. Here, we review recent knowledge of the extrinsic determinants of LHON expression, including lifestyle, dietary supplements, common chemicals, and drugs.
]]>Biomedicines doi: 10.3390/biomedicines12030583
Authors: Zenon Pogorelić Lana Stričević Sara Elezović Baloević Jakov Todorić Dražen Budimir
Aim: Triclosan is an antiseptic substance that has been shown in preclinical studies to reduce bacterial load in the wound and slow bacterial growth by inhibiting fatty acid synthesis. It is claimed that the coating protects against colonization of the tissue around the suture. This study aimed to compare the safety and efficacy of triclosan-coated polydioxanone versus uncoated polydioxanone sutures for the prevention of surgical site infections (SSIs) following hypospadias repair in children. Methods: The medical records of 550 children who underwent hypospadias repair between 1 January 2014 and 31 December 2023 were retrospectively analyzed. The patients included in the study were divided into two groups. The first group consisted of the patients in whom polydioxanone (PDS II) was used (n = 262), while in the patients of the second group (n = 288), triclosan-coated polydioxanone (PDS Plus) was used for hypospadias repair. Secondary outcomes were defined as the occurrence of early and late complications, the number of readmissions within 30 days after surgery (ReAd), unplanned return to the operating room (uROR), and repeat operations. Results: The median age of all children enrolled in the study was 16 (IQR 14, 20) months. The patients in whom PDS Plus was used for hypospadias repair had a significantly lower number of SSIs than the patients in whom PDS II was used (n = 18 (6.9%) vs. n = 4 (1.4%), p < 0.001). Wound infection led to wound dehiscence in 10 of 18 patients from the PDS II group, while all four wound infections from the PDS Plus group led to wound dehiscence (p = 0.07). The number of postoperative urethrocutaneous fistulas was significantly lower in the patients in whom PDS Plus was used (13.7% vs. 8.3%, p = 0.042). The incidence of late complications did not differ between the study groups: meatal stenosis (p = 0.944), residual chordee (p = 0.107), urethral stricture (p = 0.196), scarring (p = 0.351) and urinary discomfort (p = 0.713). There were no cases of uROR in either group. The ReAd rate was low in both groups (n = 5 (1.9%) vs. n = 2 (0.6%), p = 0.266). The frequency of reoperations was lower in the group of patients treated with PDS Plus than in the group of patients treated with PDS II (11.1% vs. 20.6%; p = 0.03). Conclusion: The use of PDS Plus in hypospadias surgery significantly reduces the incidence of SSI, postoperative fistulas, and reoperation rates compared to PDS II.
]]>Biomedicines doi: 10.3390/biomedicines12030582
Authors: Erisvaldo Amarante de Araújo Fernando Sabia Tallo Alex Sandro Felisberto Oliveira Gustavo Saad Silva El Toghlobi Rafael Augusto Arantes Rafael Balsimelli Bruno Kehrwald-Balsimelli Bianca Lorayne de Almeida Viana Fernanda Sakata Matuda Lucas Antonio Duarte Nicolau Jand Venes Rolim Medeiros Adriano Caixeta Murched Omar Taha Walter José Gomes Afonso Caricati-Neto Francisco Sandro Menezes-Rodrigues
Defined as systemic hypotension caused by intense vasodilation due to the loss of systemic vascular resistance, vasoplegic syndrome (VS) is associated with elevated morbidity and mortality in humans. Although vasopressors such as norepinephrine and vasopressin are the first-choice drugs for VS treatment, several other drugs such as methylene blue (MB) can be used as adjuvant therapy including rescue therapy. To develop new pharmacological strategies to reduce the risk of VS, we investigated the effects of treatments with MB (2 mg/kg/IV), omeprazole (OME, 10 mg/kg/IV), and their combination in an animal model of cardiac ischemia–reperfusion (CIR). The ventricular arrhythmia (VA), atrioventricular block (AVB), and lethality (LET) incidence rates caused by CIR (evaluated via ECG) and serum levels of the cardiac lesion biomarkers creatine kinase–MB (CK-MB) and troponin I (TnI) in adult rats pretreated with saline solution 0.9% and submitted to CIR (SS + CIR group) were compared to those pretreated with MB (MB + CIR group), OME (OME + CIR group), or the MB + OME combination (MB + OME + CIR group). The AVB and LET incidence rates in the MB + CIR (100%), OME + CIR (100%), and MB + OME + CIR (100%) groups were significantly higher compared to the SS + CIR group (60%). The serum level of CK-MB in these groups were also significantly higher compared to the SS + CIR group, demonstrating that the treatments before CIR with MB, OME, and MB + OME produced similar effects in relation to cardiac function and the occurrence of lesions. These results demonstrate that the treatment of animals subjected to the CIR protocol with OME produced the same effects promoted by the treatment with MB, which may suggest the possibility of using OME alone or in combination with MB in medical clinics in treatment of VS.
]]>Biomedicines doi: 10.3390/biomedicines12030581
Authors: Jaume Alijotas-Reig Ariadna Anunciacion-Llunell Enrique Esteve-Valverde Stephanie Morales-Pérez Sergio Rivero-Santana Jaume Trapé Laura González-García Domingo Ruiz Joana Marques-Soares Francesc Miro-Mur
In Long COVID, dysfunction in the pituitary–adrenal axis and alterations in immune cells and inflammatory status are warned against. We performed a prospective study in a cohort of 42 patients who suffered COVID-19 at least 6 months before attending the Long COVID unit at Althaia Hospital. Based on Post-COVID Functional Status, 29 patients were diagnosed with Long COVID, while 13 were deemed as recovered. The hormones of the pituitary–adrenal axis, adrenocorticotropin stimulation test, and immune cell profiles and inflammatory markers were examined. Patients with Long COVID had significantly lower EuroQol and higher mMRC scores compared to the recovered individuals. Their symptoms included fatigue, myalgia, arthralgia, persistent coughing, a persistent sore throat, dyspnoea, a lack of concentration, and anxiety. We observed the physiological levels of cortisol and adrenocorticotropin in individuals with or without Long COVID. The results of the adrenocorticotropin stimulation test were similar between both groups. The absolute number of neutrophils was lower in the Long COVID patients compared to recovered individuals (p < 0.05). The total count of B lymphocytes remained consistent, but Long COVID patients had a higher percentage of mature B cells compared to recovered participants (p < 0.05) and exhibited a higher percentage of circulating resident memory CD8+ T cells (p < 0.05) and Treg-expressing exonucleases (p < 0.05). Our findings did not identify adrenal dysfunction related to Long COVID, nor an association between adrenal function and clinical symptoms. The data indicated a dysregulation in certain immune cells, pointing to immune activation. No overt hyperinflammation was observed in the Long COVID group.
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